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Skin Test Accurately Detects Parkinson’s, Other Neurodegenerative Disorders
A simple skin biopsy test is able to detect an abnormal form of alpha-synuclein with high accuracy in individuals with neurodegenerative disorders such as Parkinson’s disease (PD).
Synucleinopathies include PD, dementia with Lewy bodies (DLB), multiple system atrophy (MSA), and pure autonomic failure (PAF).
“Each year, there are nearly 200,000 people in the U.S. who face a diagnosis of Parkinson’s disease, dementia with Lewy bodies, and related disorders,” study investigator Christopher H. Gibbons, MD, professor of neurology at Harvard Medical School in Boston, said in a press release.
He explained that patients often experience delays in diagnosis or are misdiagnosed due to the complexity of synucleinopathies.
“With a simple, minimally invasive skin biopsy test, this blinded, multicenter study demonstrated how we can more objectively identify the underlying pathology of synucleinopathies and offer better diagnostic answers and care for patients.”
The findings were published online on March 20 in JAMA.
An Urgent Priority
Affecting an estimated 2.5 million people in the United States, synucleinopathies are progressive neurodegenerative diseases with varying prognoses, so identifying a reliable diagnostic biomarker is an “urgent unmet priority,” the researchers noted.
The disorders share some symptoms such as tremors and cognitive changes, and all are characterized by P-SYN, an abnormal protein found in the cutaneous nerve fibers.
The study included 428 adults aged 40-99 years (mean age, 70 years) recruited from 30 academic and community-based neurology practices across the United States, with 277 diagnosed with PD, DLB, MSA, or PAF. It also included a control group of 120 participants with no symptoms suggestive of synucleinopathy.
Investigators used the commercially available Syn-One Test, developed in 2019 by CND Life Sciences, to analyze levels of P-SYN via 3-mm punch skin biopsies from each participant.
The test detected P-SYN in 95.5% of study participants overall, including 89 of 96 (92.7%) with PD, 54 of 55 (98.2%) with MSA, 48 of 50 (96%) with DLB, 22 of 22 (100%) with PAF, and 4 of 120 (3.3%) of the controls with no synucleinopathy.
The investigators said it is possible that some of the controls who tested positive had a subclinical form of synucleinopathy, which would explain the false positives.
Study limitations include clinical consensus diagnostic criteria without video or autopsy confirmation, a lack of genetic testing on participants (some genetic forms of PD do not have alpha-synuclein deposition), and the fact that controls were younger than those in disease groups.
“Further research is needed in unselected clinical populations to externally validate the findings and fully characterize the potential role of skin biopsy detection of P-SYN in clinical care,” the authors wrote.
Syn-One is not approved by the US Food and Drug Administration as a diagnostic test for PD but is available as a pathologic assay that determines whether a tissue sample contains phosphorylated alpha-synuclein and can be billed through Medicare.
The study was funded by the National Institutes of Health. Dr. Gibbons reported having stock options in CND Life Sciences outside the submitted work. Other disclosures are noted in the original article.
A version of this article appeared on Medscape.com.
A simple skin biopsy test is able to detect an abnormal form of alpha-synuclein with high accuracy in individuals with neurodegenerative disorders such as Parkinson’s disease (PD).
Synucleinopathies include PD, dementia with Lewy bodies (DLB), multiple system atrophy (MSA), and pure autonomic failure (PAF).
“Each year, there are nearly 200,000 people in the U.S. who face a diagnosis of Parkinson’s disease, dementia with Lewy bodies, and related disorders,” study investigator Christopher H. Gibbons, MD, professor of neurology at Harvard Medical School in Boston, said in a press release.
He explained that patients often experience delays in diagnosis or are misdiagnosed due to the complexity of synucleinopathies.
“With a simple, minimally invasive skin biopsy test, this blinded, multicenter study demonstrated how we can more objectively identify the underlying pathology of synucleinopathies and offer better diagnostic answers and care for patients.”
The findings were published online on March 20 in JAMA.
An Urgent Priority
Affecting an estimated 2.5 million people in the United States, synucleinopathies are progressive neurodegenerative diseases with varying prognoses, so identifying a reliable diagnostic biomarker is an “urgent unmet priority,” the researchers noted.
The disorders share some symptoms such as tremors and cognitive changes, and all are characterized by P-SYN, an abnormal protein found in the cutaneous nerve fibers.
The study included 428 adults aged 40-99 years (mean age, 70 years) recruited from 30 academic and community-based neurology practices across the United States, with 277 diagnosed with PD, DLB, MSA, or PAF. It also included a control group of 120 participants with no symptoms suggestive of synucleinopathy.
Investigators used the commercially available Syn-One Test, developed in 2019 by CND Life Sciences, to analyze levels of P-SYN via 3-mm punch skin biopsies from each participant.
The test detected P-SYN in 95.5% of study participants overall, including 89 of 96 (92.7%) with PD, 54 of 55 (98.2%) with MSA, 48 of 50 (96%) with DLB, 22 of 22 (100%) with PAF, and 4 of 120 (3.3%) of the controls with no synucleinopathy.
The investigators said it is possible that some of the controls who tested positive had a subclinical form of synucleinopathy, which would explain the false positives.
Study limitations include clinical consensus diagnostic criteria without video or autopsy confirmation, a lack of genetic testing on participants (some genetic forms of PD do not have alpha-synuclein deposition), and the fact that controls were younger than those in disease groups.
“Further research is needed in unselected clinical populations to externally validate the findings and fully characterize the potential role of skin biopsy detection of P-SYN in clinical care,” the authors wrote.
Syn-One is not approved by the US Food and Drug Administration as a diagnostic test for PD but is available as a pathologic assay that determines whether a tissue sample contains phosphorylated alpha-synuclein and can be billed through Medicare.
The study was funded by the National Institutes of Health. Dr. Gibbons reported having stock options in CND Life Sciences outside the submitted work. Other disclosures are noted in the original article.
A version of this article appeared on Medscape.com.
A simple skin biopsy test is able to detect an abnormal form of alpha-synuclein with high accuracy in individuals with neurodegenerative disorders such as Parkinson’s disease (PD).
Synucleinopathies include PD, dementia with Lewy bodies (DLB), multiple system atrophy (MSA), and pure autonomic failure (PAF).
“Each year, there are nearly 200,000 people in the U.S. who face a diagnosis of Parkinson’s disease, dementia with Lewy bodies, and related disorders,” study investigator Christopher H. Gibbons, MD, professor of neurology at Harvard Medical School in Boston, said in a press release.
He explained that patients often experience delays in diagnosis or are misdiagnosed due to the complexity of synucleinopathies.
“With a simple, minimally invasive skin biopsy test, this blinded, multicenter study demonstrated how we can more objectively identify the underlying pathology of synucleinopathies and offer better diagnostic answers and care for patients.”
The findings were published online on March 20 in JAMA.
An Urgent Priority
Affecting an estimated 2.5 million people in the United States, synucleinopathies are progressive neurodegenerative diseases with varying prognoses, so identifying a reliable diagnostic biomarker is an “urgent unmet priority,” the researchers noted.
The disorders share some symptoms such as tremors and cognitive changes, and all are characterized by P-SYN, an abnormal protein found in the cutaneous nerve fibers.
The study included 428 adults aged 40-99 years (mean age, 70 years) recruited from 30 academic and community-based neurology practices across the United States, with 277 diagnosed with PD, DLB, MSA, or PAF. It also included a control group of 120 participants with no symptoms suggestive of synucleinopathy.
Investigators used the commercially available Syn-One Test, developed in 2019 by CND Life Sciences, to analyze levels of P-SYN via 3-mm punch skin biopsies from each participant.
The test detected P-SYN in 95.5% of study participants overall, including 89 of 96 (92.7%) with PD, 54 of 55 (98.2%) with MSA, 48 of 50 (96%) with DLB, 22 of 22 (100%) with PAF, and 4 of 120 (3.3%) of the controls with no synucleinopathy.
The investigators said it is possible that some of the controls who tested positive had a subclinical form of synucleinopathy, which would explain the false positives.
Study limitations include clinical consensus diagnostic criteria without video or autopsy confirmation, a lack of genetic testing on participants (some genetic forms of PD do not have alpha-synuclein deposition), and the fact that controls were younger than those in disease groups.
“Further research is needed in unselected clinical populations to externally validate the findings and fully characterize the potential role of skin biopsy detection of P-SYN in clinical care,” the authors wrote.
Syn-One is not approved by the US Food and Drug Administration as a diagnostic test for PD but is available as a pathologic assay that determines whether a tissue sample contains phosphorylated alpha-synuclein and can be billed through Medicare.
The study was funded by the National Institutes of Health. Dr. Gibbons reported having stock options in CND Life Sciences outside the submitted work. Other disclosures are noted in the original article.
A version of this article appeared on Medscape.com.
Glucose Level Fluctuations Affect Cognition in T1D
TOPLINE:
Naturally occurring glucose fluctuations affect cognitive function in people with type 1 diabetes, according to a new study. It matters less whether glucose is considerably higher or lower than the patient’s usual glucose level. Rather,
METHODOLOGY:
- The investigators used continuous glucose monitoring (CGM) digital sensors and smartphone-based cognitive tests (cognitive ecological momentary assessment [EMA]) to collect repeated, high-frequency glucose and cognitive data. Glucose data were collected every 5 minutes; cognitive data were collected three times daily for 15 days as participants went about their daily lives.
- The study included 200 participants (mean [standard deviation] age, 47.5 [15.6] years; 53.5% female; 86% White; mean A1c, 7.5 mmol/mol [1.3]).
- Using CGM and EMA, the researchers obtained “intensive” longitudinal measurements of glucose as well as cognition (processing speed and sustained attention).
- Hierarchical Bayesian modeling estimated dynamic, within-person associations between glucose and cognition, and data-driven lasso regression identified identify clinical characteristics that predicted differences from person to person in cognitive vulnerability to glucose fluctuations.
TAKEAWAY:
- Cognitive performance was reduced both at low and high glucose levels, “reflecting vulnerability to glucose fluctuations.”
- Large glucose fluctuations were associated with slower as well as less accurate processing speed, although slight glucose elevations (relative to the individual’s own means) were associated with faster processing speed, regardless of the absolute level (eg, euglycemic vs hyperglycemic) of those means.
- By contrast, glucose fluctuations were unrelated to sustained attention.
- The researchers identified seven clinical characteristics that predicted individual differences in cognitive vulnerability to glucose fluctuations: Older age, time in hypoglycemia, lifetime severe hypoglycemic events, microvascular complications, glucose variability, fatigue, and larger neck circumference.
IN PRACTICE:
“Our results demonstrate that people can differ a lot from one another in how their brains are impacted by glucose,” co-senior author Laura Germine, PhD, director of the Laboratory for Brain and Cognitive Health Technology, McLean Hospital, Boston, said in a news release. “We found that minimizing glucose fluctuations in daily life is important for optimizing processing speed, and this is especially true for people who are older or have other diabetes-related health conditions.”
SOURCE:
Zoë Hawks, PhD, research investigator, McLean Hospital, Boston, was the lead and corresponding author on the study. It was published online on March 18 in Digital Medicine.
LIMITATIONS:
The researchers required 24-hour access to a smartphone with reliable Internet access, which might have biased sampling toward people of higher economic status. Moreover, the present sample was predominantly White and non-Hispanic, so findings may not be generalizable to other populations.
DISCLOSURES:
The research was supported by grants from the National Institutes of Health, the Brain and Behavior Research Foundation, and the Alzheimer’s Association. Dr. Hawks received consulting fees from Blueprint Health. The other authors’ disclosures were listed in the original paper.
A version of this article appeared on Medscape.com.
TOPLINE:
Naturally occurring glucose fluctuations affect cognitive function in people with type 1 diabetes, according to a new study. It matters less whether glucose is considerably higher or lower than the patient’s usual glucose level. Rather,
METHODOLOGY:
- The investigators used continuous glucose monitoring (CGM) digital sensors and smartphone-based cognitive tests (cognitive ecological momentary assessment [EMA]) to collect repeated, high-frequency glucose and cognitive data. Glucose data were collected every 5 minutes; cognitive data were collected three times daily for 15 days as participants went about their daily lives.
- The study included 200 participants (mean [standard deviation] age, 47.5 [15.6] years; 53.5% female; 86% White; mean A1c, 7.5 mmol/mol [1.3]).
- Using CGM and EMA, the researchers obtained “intensive” longitudinal measurements of glucose as well as cognition (processing speed and sustained attention).
- Hierarchical Bayesian modeling estimated dynamic, within-person associations between glucose and cognition, and data-driven lasso regression identified identify clinical characteristics that predicted differences from person to person in cognitive vulnerability to glucose fluctuations.
TAKEAWAY:
- Cognitive performance was reduced both at low and high glucose levels, “reflecting vulnerability to glucose fluctuations.”
- Large glucose fluctuations were associated with slower as well as less accurate processing speed, although slight glucose elevations (relative to the individual’s own means) were associated with faster processing speed, regardless of the absolute level (eg, euglycemic vs hyperglycemic) of those means.
- By contrast, glucose fluctuations were unrelated to sustained attention.
- The researchers identified seven clinical characteristics that predicted individual differences in cognitive vulnerability to glucose fluctuations: Older age, time in hypoglycemia, lifetime severe hypoglycemic events, microvascular complications, glucose variability, fatigue, and larger neck circumference.
IN PRACTICE:
“Our results demonstrate that people can differ a lot from one another in how their brains are impacted by glucose,” co-senior author Laura Germine, PhD, director of the Laboratory for Brain and Cognitive Health Technology, McLean Hospital, Boston, said in a news release. “We found that minimizing glucose fluctuations in daily life is important for optimizing processing speed, and this is especially true for people who are older or have other diabetes-related health conditions.”
SOURCE:
Zoë Hawks, PhD, research investigator, McLean Hospital, Boston, was the lead and corresponding author on the study. It was published online on March 18 in Digital Medicine.
LIMITATIONS:
The researchers required 24-hour access to a smartphone with reliable Internet access, which might have biased sampling toward people of higher economic status. Moreover, the present sample was predominantly White and non-Hispanic, so findings may not be generalizable to other populations.
DISCLOSURES:
The research was supported by grants from the National Institutes of Health, the Brain and Behavior Research Foundation, and the Alzheimer’s Association. Dr. Hawks received consulting fees from Blueprint Health. The other authors’ disclosures were listed in the original paper.
A version of this article appeared on Medscape.com.
TOPLINE:
Naturally occurring glucose fluctuations affect cognitive function in people with type 1 diabetes, according to a new study. It matters less whether glucose is considerably higher or lower than the patient’s usual glucose level. Rather,
METHODOLOGY:
- The investigators used continuous glucose monitoring (CGM) digital sensors and smartphone-based cognitive tests (cognitive ecological momentary assessment [EMA]) to collect repeated, high-frequency glucose and cognitive data. Glucose data were collected every 5 minutes; cognitive data were collected three times daily for 15 days as participants went about their daily lives.
- The study included 200 participants (mean [standard deviation] age, 47.5 [15.6] years; 53.5% female; 86% White; mean A1c, 7.5 mmol/mol [1.3]).
- Using CGM and EMA, the researchers obtained “intensive” longitudinal measurements of glucose as well as cognition (processing speed and sustained attention).
- Hierarchical Bayesian modeling estimated dynamic, within-person associations between glucose and cognition, and data-driven lasso regression identified identify clinical characteristics that predicted differences from person to person in cognitive vulnerability to glucose fluctuations.
TAKEAWAY:
- Cognitive performance was reduced both at low and high glucose levels, “reflecting vulnerability to glucose fluctuations.”
- Large glucose fluctuations were associated with slower as well as less accurate processing speed, although slight glucose elevations (relative to the individual’s own means) were associated with faster processing speed, regardless of the absolute level (eg, euglycemic vs hyperglycemic) of those means.
- By contrast, glucose fluctuations were unrelated to sustained attention.
- The researchers identified seven clinical characteristics that predicted individual differences in cognitive vulnerability to glucose fluctuations: Older age, time in hypoglycemia, lifetime severe hypoglycemic events, microvascular complications, glucose variability, fatigue, and larger neck circumference.
IN PRACTICE:
“Our results demonstrate that people can differ a lot from one another in how their brains are impacted by glucose,” co-senior author Laura Germine, PhD, director of the Laboratory for Brain and Cognitive Health Technology, McLean Hospital, Boston, said in a news release. “We found that minimizing glucose fluctuations in daily life is important for optimizing processing speed, and this is especially true for people who are older or have other diabetes-related health conditions.”
SOURCE:
Zoë Hawks, PhD, research investigator, McLean Hospital, Boston, was the lead and corresponding author on the study. It was published online on March 18 in Digital Medicine.
LIMITATIONS:
The researchers required 24-hour access to a smartphone with reliable Internet access, which might have biased sampling toward people of higher economic status. Moreover, the present sample was predominantly White and non-Hispanic, so findings may not be generalizable to other populations.
DISCLOSURES:
The research was supported by grants from the National Institutes of Health, the Brain and Behavior Research Foundation, and the Alzheimer’s Association. Dr. Hawks received consulting fees from Blueprint Health. The other authors’ disclosures were listed in the original paper.
A version of this article appeared on Medscape.com.
Disadvantaged Neighborhoods Tied to Higher Dementia Risk, Brain Aging
Living in a disadvantaged neighborhood is associated with accelerated brain aging and a higher risk for early dementia, regardless of income level or education, new research suggested.
“If you want to prevent dementia and you’re not asking someone about their neighborhood, you’re missing information that’s important to know,” lead author Aaron Reuben, PhD, postdoctoral scholar in neuropsychology and environmental health at Duke University, Durham, North Carolina, said in a news release.
The study was published online in Alzheimer’s & Dementia.
Higher Risk in Men
Few interventions exist to halt or delay the progression of Alzheimer’s disease and related dementias (ADRD), which has increasingly led to a focus on primary prevention.
Although previous research pointed to a link between socioeconomically disadvantaged neighborhoods and a greater risk for cognitive deficits, mild cognitive impairment, dementia, and poor brain health, the timeline for the emergence of that risk is unknown.
To fill in the gaps, investigators studied data on all 1.4 million New Zealand residents, dividing neighborhoods into quintiles based on level of disadvantage (assessed by the New Zealand Index of Deprivation) to see whether dementia diagnoses followed neighborhood socioeconomic gradients.
After adjusting for covariates, they found that overall, those living in disadvantaged areas were slightly more likely to develop dementia across the 20-year study period (adjusted hazard ratio [HR], 1.09; 95% CI, 1.08-1.10).
The more disadvantaged the neighborhood, the higher the dementia risk, with a 43% higher risk for ADRD among those in the highest quintile than among those in the lowest quintile (HR, 1.43; 95% CI, 1.36-1.49).
The effect was larger in men than in women and in younger vs older individuals, with the youngest age group showing 21% greater risk in women and 26% greater risk in men vs the oldest age group.
Dementia Prevention Starts Early
Researchers then turned to the Dunedin Study, a cohort of 938 New Zealanders (50% female) followed from birth to age 45 to track their psychological, social, and physiological health with brain scans, memory tests, and cognitive self-assessments.
The analysis suggested that by age 45, those living in more disadvantaged neighborhoods across adulthood had accumulated a significantly greater number of midlife risk factors for later ADRD.
They also had worse structural brain integrity, with each standard deviation increase in neighborhood disadvantage resulting in a thinner cortex, greater white matter hyperintensities volume, and older brain age.
Those living in poorer areas had lower cognitive test scores, reported more issues with everyday cognitive function, and showed a greater reduction in IQ from childhood to midlife. Analysis of brain scans also revealed mean brain ages 2.98 years older than those living in the least disadvantaged areas (P = .001).
Limitations included the study’s observational design, which could not establish causation, and the fact that the researchers did not have access to individual-level socioeconomic information for the entire population. Additionally, brain-integrity measures in the Dunedin Study were largely cross-sectional.
“If you want to truly prevent dementia, you’ve got to start early because 20 years before anyone will get a diagnosis, we’re seeing dementia’s emergence,” Dr. Reuben said. “And it could be even earlier.”
Funding for the study was provided by the National Institutes for Health; UK Medical Research Council; Health Research Council of New Zealand; Brain Research New Zealand; New Zealand Ministry of Business, Innovation, & Employment; and the Duke University and the University of North Carolina Alzheimer’s Disease Research Center. The authors declared no relevant financial relationships.
A version of this article appeared on Medscape.com.
Living in a disadvantaged neighborhood is associated with accelerated brain aging and a higher risk for early dementia, regardless of income level or education, new research suggested.
“If you want to prevent dementia and you’re not asking someone about their neighborhood, you’re missing information that’s important to know,” lead author Aaron Reuben, PhD, postdoctoral scholar in neuropsychology and environmental health at Duke University, Durham, North Carolina, said in a news release.
The study was published online in Alzheimer’s & Dementia.
Higher Risk in Men
Few interventions exist to halt or delay the progression of Alzheimer’s disease and related dementias (ADRD), which has increasingly led to a focus on primary prevention.
Although previous research pointed to a link between socioeconomically disadvantaged neighborhoods and a greater risk for cognitive deficits, mild cognitive impairment, dementia, and poor brain health, the timeline for the emergence of that risk is unknown.
To fill in the gaps, investigators studied data on all 1.4 million New Zealand residents, dividing neighborhoods into quintiles based on level of disadvantage (assessed by the New Zealand Index of Deprivation) to see whether dementia diagnoses followed neighborhood socioeconomic gradients.
After adjusting for covariates, they found that overall, those living in disadvantaged areas were slightly more likely to develop dementia across the 20-year study period (adjusted hazard ratio [HR], 1.09; 95% CI, 1.08-1.10).
The more disadvantaged the neighborhood, the higher the dementia risk, with a 43% higher risk for ADRD among those in the highest quintile than among those in the lowest quintile (HR, 1.43; 95% CI, 1.36-1.49).
The effect was larger in men than in women and in younger vs older individuals, with the youngest age group showing 21% greater risk in women and 26% greater risk in men vs the oldest age group.
Dementia Prevention Starts Early
Researchers then turned to the Dunedin Study, a cohort of 938 New Zealanders (50% female) followed from birth to age 45 to track their psychological, social, and physiological health with brain scans, memory tests, and cognitive self-assessments.
The analysis suggested that by age 45, those living in more disadvantaged neighborhoods across adulthood had accumulated a significantly greater number of midlife risk factors for later ADRD.
They also had worse structural brain integrity, with each standard deviation increase in neighborhood disadvantage resulting in a thinner cortex, greater white matter hyperintensities volume, and older brain age.
Those living in poorer areas had lower cognitive test scores, reported more issues with everyday cognitive function, and showed a greater reduction in IQ from childhood to midlife. Analysis of brain scans also revealed mean brain ages 2.98 years older than those living in the least disadvantaged areas (P = .001).
Limitations included the study’s observational design, which could not establish causation, and the fact that the researchers did not have access to individual-level socioeconomic information for the entire population. Additionally, brain-integrity measures in the Dunedin Study were largely cross-sectional.
“If you want to truly prevent dementia, you’ve got to start early because 20 years before anyone will get a diagnosis, we’re seeing dementia’s emergence,” Dr. Reuben said. “And it could be even earlier.”
Funding for the study was provided by the National Institutes for Health; UK Medical Research Council; Health Research Council of New Zealand; Brain Research New Zealand; New Zealand Ministry of Business, Innovation, & Employment; and the Duke University and the University of North Carolina Alzheimer’s Disease Research Center. The authors declared no relevant financial relationships.
A version of this article appeared on Medscape.com.
Living in a disadvantaged neighborhood is associated with accelerated brain aging and a higher risk for early dementia, regardless of income level or education, new research suggested.
“If you want to prevent dementia and you’re not asking someone about their neighborhood, you’re missing information that’s important to know,” lead author Aaron Reuben, PhD, postdoctoral scholar in neuropsychology and environmental health at Duke University, Durham, North Carolina, said in a news release.
The study was published online in Alzheimer’s & Dementia.
Higher Risk in Men
Few interventions exist to halt or delay the progression of Alzheimer’s disease and related dementias (ADRD), which has increasingly led to a focus on primary prevention.
Although previous research pointed to a link between socioeconomically disadvantaged neighborhoods and a greater risk for cognitive deficits, mild cognitive impairment, dementia, and poor brain health, the timeline for the emergence of that risk is unknown.
To fill in the gaps, investigators studied data on all 1.4 million New Zealand residents, dividing neighborhoods into quintiles based on level of disadvantage (assessed by the New Zealand Index of Deprivation) to see whether dementia diagnoses followed neighborhood socioeconomic gradients.
After adjusting for covariates, they found that overall, those living in disadvantaged areas were slightly more likely to develop dementia across the 20-year study period (adjusted hazard ratio [HR], 1.09; 95% CI, 1.08-1.10).
The more disadvantaged the neighborhood, the higher the dementia risk, with a 43% higher risk for ADRD among those in the highest quintile than among those in the lowest quintile (HR, 1.43; 95% CI, 1.36-1.49).
The effect was larger in men than in women and in younger vs older individuals, with the youngest age group showing 21% greater risk in women and 26% greater risk in men vs the oldest age group.
Dementia Prevention Starts Early
Researchers then turned to the Dunedin Study, a cohort of 938 New Zealanders (50% female) followed from birth to age 45 to track their psychological, social, and physiological health with brain scans, memory tests, and cognitive self-assessments.
The analysis suggested that by age 45, those living in more disadvantaged neighborhoods across adulthood had accumulated a significantly greater number of midlife risk factors for later ADRD.
They also had worse structural brain integrity, with each standard deviation increase in neighborhood disadvantage resulting in a thinner cortex, greater white matter hyperintensities volume, and older brain age.
Those living in poorer areas had lower cognitive test scores, reported more issues with everyday cognitive function, and showed a greater reduction in IQ from childhood to midlife. Analysis of brain scans also revealed mean brain ages 2.98 years older than those living in the least disadvantaged areas (P = .001).
Limitations included the study’s observational design, which could not establish causation, and the fact that the researchers did not have access to individual-level socioeconomic information for the entire population. Additionally, brain-integrity measures in the Dunedin Study were largely cross-sectional.
“If you want to truly prevent dementia, you’ve got to start early because 20 years before anyone will get a diagnosis, we’re seeing dementia’s emergence,” Dr. Reuben said. “And it could be even earlier.”
Funding for the study was provided by the National Institutes for Health; UK Medical Research Council; Health Research Council of New Zealand; Brain Research New Zealand; New Zealand Ministry of Business, Innovation, & Employment; and the Duke University and the University of North Carolina Alzheimer’s Disease Research Center. The authors declared no relevant financial relationships.
A version of this article appeared on Medscape.com.
FROM ALZHEIMER’S AND DEMENTIA
FDA Issues New Guidance for Early Alzheimer’s Drug Development
The agency’s draft guidance is the first update since 2018 for products aimed at the earliest stages of the disease, which the FDA defines as stages 1, 2, and 3. Such guidance — when it is made final, after public comment closes in mid-May — is considered a template that will guide discussions between the FDA and drug makers and help determine the structure of clinical trials.
It is considered the FDA’s “current thinking on the topic,” and should not be construed as “legally enforceable responsibilities,” the FDA document, which was published March 12, noted.
In a statement to this news agency, the Alzheimer’s Association said it “is fully supportive of the FDA’s revised draft guidance.”
The association is enthusiastic about the agency’s encouragement of “the use of biologically based diagnostic criteria that are grounded in a contemporary understanding of the pathophysiology and evolution” of Alzheimer’s disease, Rebecca M. Edelmayer, PhD, senior director of scientific engagement for the Alzheimer’s Association, said in the statement.
Dr. Edelmayer noted that an Alzheimer’s Association work group is “leading the process of defining and building consensus for biologically based diagnostic and staging criteria for Alzheimer’s disease.
A New POV
The FDA noted that “it is expected that biomarker evidence of disease will establish the reliable diagnosis of subjects in trials of early Alzheimer’s disease.” This is crucial when many individuals in the earliest phases of Alzheimer’s disease may have mild cognitive decline but no functional decline, the agency added.
In 2018, the FDA suggested that biomarker evidence of disease might only play a role in identifying trial participants but should not be a defining element.
In another shift away from 2018 guidance, the FDA gave more credence to surrogate endpoints as measures of a drug’s efficacy for early disease.
“Surrogate endpoints or intermediate clinical endpoints that do not directly measure clinical benefit but that are considered reasonably likely to predict clinical benefit may support an accelerated approval,” the agency noted.
The FDA added that it “has considered a reduction of the brain amyloid beta burden, as assessed by positron emission tomography, to be a surrogate endpoint that is ‘reasonably likely to predict clinical benefit,’ ” noting that this endpoint was used as a basis for accelerated approval for the monoclonal antibodies lecanemab (Leqembi) and aducanumab (Aduhelm).
“The FDA has determined there is substantial evidence that reduction of amyloid beta plaques in the brain is reasonably likely to predict important clinical benefits to patients,” said Dr. Edelmayer, adding the agency’s “determination is correct.”
However, she noted, “’reasonably likely’ is not a guarantee, and long-term, real-world data in representative populations is required to provide more conclusive evidence,” which is why the FDA requires post-approval studies for accelerated approvals.
A Faster Pathway to Approval
The agency noted that clinical outcomes should also be measured in trials of products seeking accelerated approval, “to assess early clinical changes that may potentially provide support for any changes observed on biomarkers.”
Indeed, it’s not always a slam-dunk for drugs that may show positive effects on biomarkers. The FDA is taking a closer look at donanemab for early symptomatic Alzheimer’s disease. Patients were enrolled based on PET-positive amyloid or tau, but efficacy was evaluated based on cognition and functional measures.
Earlier this month the agency postponed an approval decision and instead will convene an advisory panel meeting to assess overall safety and efficacy and the unique trial design, which allowed patients to stop treatment based on amyloid levels.
The FDA emphasized throughout its guidance document that it is trying to find a faster pathway to approval for therapies for early Alzheimer’s disease. If conventional approaches for testing therapeutics were used in early disease it might “take longer to establish a clinically meaningful treatment effect” because of the “minimal or absent cognitive and functional deficits seen in those stages of the disease,” the agency wrote.
The use of surrogate endpoints “may allow for shorter trial durations,” the FDA added.
Dr. Edelmayer applauded the agency’s efforts to shorten the process. “Finding ways to make the trials shorter and easier to conduct, without sacrificing scientific rigor or patient safety, is a very worthwhile thing to do,” she said.
The FDA noted that a key principle in developing guidance for early Alzheimer’s disease therapies is that treatment “must begin before there are overt clinical symptoms.”
“We enthusiastically support this idea,” said Dr. Edelmeyer. “Prevention of Alzheimer’s dementia is possible through changing the course, stopping the progression, and eventually interrupting the causes of the disease, most likely through a combination of lifestyle/behavior choices and pharmaceutical intervention,” she added.
A version of this article appeared on Medscape.com.
The agency’s draft guidance is the first update since 2018 for products aimed at the earliest stages of the disease, which the FDA defines as stages 1, 2, and 3. Such guidance — when it is made final, after public comment closes in mid-May — is considered a template that will guide discussions between the FDA and drug makers and help determine the structure of clinical trials.
It is considered the FDA’s “current thinking on the topic,” and should not be construed as “legally enforceable responsibilities,” the FDA document, which was published March 12, noted.
In a statement to this news agency, the Alzheimer’s Association said it “is fully supportive of the FDA’s revised draft guidance.”
The association is enthusiastic about the agency’s encouragement of “the use of biologically based diagnostic criteria that are grounded in a contemporary understanding of the pathophysiology and evolution” of Alzheimer’s disease, Rebecca M. Edelmayer, PhD, senior director of scientific engagement for the Alzheimer’s Association, said in the statement.
Dr. Edelmayer noted that an Alzheimer’s Association work group is “leading the process of defining and building consensus for biologically based diagnostic and staging criteria for Alzheimer’s disease.
A New POV
The FDA noted that “it is expected that biomarker evidence of disease will establish the reliable diagnosis of subjects in trials of early Alzheimer’s disease.” This is crucial when many individuals in the earliest phases of Alzheimer’s disease may have mild cognitive decline but no functional decline, the agency added.
In 2018, the FDA suggested that biomarker evidence of disease might only play a role in identifying trial participants but should not be a defining element.
In another shift away from 2018 guidance, the FDA gave more credence to surrogate endpoints as measures of a drug’s efficacy for early disease.
“Surrogate endpoints or intermediate clinical endpoints that do not directly measure clinical benefit but that are considered reasonably likely to predict clinical benefit may support an accelerated approval,” the agency noted.
The FDA added that it “has considered a reduction of the brain amyloid beta burden, as assessed by positron emission tomography, to be a surrogate endpoint that is ‘reasonably likely to predict clinical benefit,’ ” noting that this endpoint was used as a basis for accelerated approval for the monoclonal antibodies lecanemab (Leqembi) and aducanumab (Aduhelm).
“The FDA has determined there is substantial evidence that reduction of amyloid beta plaques in the brain is reasonably likely to predict important clinical benefits to patients,” said Dr. Edelmayer, adding the agency’s “determination is correct.”
However, she noted, “’reasonably likely’ is not a guarantee, and long-term, real-world data in representative populations is required to provide more conclusive evidence,” which is why the FDA requires post-approval studies for accelerated approvals.
A Faster Pathway to Approval
The agency noted that clinical outcomes should also be measured in trials of products seeking accelerated approval, “to assess early clinical changes that may potentially provide support for any changes observed on biomarkers.”
Indeed, it’s not always a slam-dunk for drugs that may show positive effects on biomarkers. The FDA is taking a closer look at donanemab for early symptomatic Alzheimer’s disease. Patients were enrolled based on PET-positive amyloid or tau, but efficacy was evaluated based on cognition and functional measures.
Earlier this month the agency postponed an approval decision and instead will convene an advisory panel meeting to assess overall safety and efficacy and the unique trial design, which allowed patients to stop treatment based on amyloid levels.
The FDA emphasized throughout its guidance document that it is trying to find a faster pathway to approval for therapies for early Alzheimer’s disease. If conventional approaches for testing therapeutics were used in early disease it might “take longer to establish a clinically meaningful treatment effect” because of the “minimal or absent cognitive and functional deficits seen in those stages of the disease,” the agency wrote.
The use of surrogate endpoints “may allow for shorter trial durations,” the FDA added.
Dr. Edelmayer applauded the agency’s efforts to shorten the process. “Finding ways to make the trials shorter and easier to conduct, without sacrificing scientific rigor or patient safety, is a very worthwhile thing to do,” she said.
The FDA noted that a key principle in developing guidance for early Alzheimer’s disease therapies is that treatment “must begin before there are overt clinical symptoms.”
“We enthusiastically support this idea,” said Dr. Edelmeyer. “Prevention of Alzheimer’s dementia is possible through changing the course, stopping the progression, and eventually interrupting the causes of the disease, most likely through a combination of lifestyle/behavior choices and pharmaceutical intervention,” she added.
A version of this article appeared on Medscape.com.
The agency’s draft guidance is the first update since 2018 for products aimed at the earliest stages of the disease, which the FDA defines as stages 1, 2, and 3. Such guidance — when it is made final, after public comment closes in mid-May — is considered a template that will guide discussions between the FDA and drug makers and help determine the structure of clinical trials.
It is considered the FDA’s “current thinking on the topic,” and should not be construed as “legally enforceable responsibilities,” the FDA document, which was published March 12, noted.
In a statement to this news agency, the Alzheimer’s Association said it “is fully supportive of the FDA’s revised draft guidance.”
The association is enthusiastic about the agency’s encouragement of “the use of biologically based diagnostic criteria that are grounded in a contemporary understanding of the pathophysiology and evolution” of Alzheimer’s disease, Rebecca M. Edelmayer, PhD, senior director of scientific engagement for the Alzheimer’s Association, said in the statement.
Dr. Edelmayer noted that an Alzheimer’s Association work group is “leading the process of defining and building consensus for biologically based diagnostic and staging criteria for Alzheimer’s disease.
A New POV
The FDA noted that “it is expected that biomarker evidence of disease will establish the reliable diagnosis of subjects in trials of early Alzheimer’s disease.” This is crucial when many individuals in the earliest phases of Alzheimer’s disease may have mild cognitive decline but no functional decline, the agency added.
In 2018, the FDA suggested that biomarker evidence of disease might only play a role in identifying trial participants but should not be a defining element.
In another shift away from 2018 guidance, the FDA gave more credence to surrogate endpoints as measures of a drug’s efficacy for early disease.
“Surrogate endpoints or intermediate clinical endpoints that do not directly measure clinical benefit but that are considered reasonably likely to predict clinical benefit may support an accelerated approval,” the agency noted.
The FDA added that it “has considered a reduction of the brain amyloid beta burden, as assessed by positron emission tomography, to be a surrogate endpoint that is ‘reasonably likely to predict clinical benefit,’ ” noting that this endpoint was used as a basis for accelerated approval for the monoclonal antibodies lecanemab (Leqembi) and aducanumab (Aduhelm).
“The FDA has determined there is substantial evidence that reduction of amyloid beta plaques in the brain is reasonably likely to predict important clinical benefits to patients,” said Dr. Edelmayer, adding the agency’s “determination is correct.”
However, she noted, “’reasonably likely’ is not a guarantee, and long-term, real-world data in representative populations is required to provide more conclusive evidence,” which is why the FDA requires post-approval studies for accelerated approvals.
A Faster Pathway to Approval
The agency noted that clinical outcomes should also be measured in trials of products seeking accelerated approval, “to assess early clinical changes that may potentially provide support for any changes observed on biomarkers.”
Indeed, it’s not always a slam-dunk for drugs that may show positive effects on biomarkers. The FDA is taking a closer look at donanemab for early symptomatic Alzheimer’s disease. Patients were enrolled based on PET-positive amyloid or tau, but efficacy was evaluated based on cognition and functional measures.
Earlier this month the agency postponed an approval decision and instead will convene an advisory panel meeting to assess overall safety and efficacy and the unique trial design, which allowed patients to stop treatment based on amyloid levels.
The FDA emphasized throughout its guidance document that it is trying to find a faster pathway to approval for therapies for early Alzheimer’s disease. If conventional approaches for testing therapeutics were used in early disease it might “take longer to establish a clinically meaningful treatment effect” because of the “minimal or absent cognitive and functional deficits seen in those stages of the disease,” the agency wrote.
The use of surrogate endpoints “may allow for shorter trial durations,” the FDA added.
Dr. Edelmayer applauded the agency’s efforts to shorten the process. “Finding ways to make the trials shorter and easier to conduct, without sacrificing scientific rigor or patient safety, is a very worthwhile thing to do,” she said.
The FDA noted that a key principle in developing guidance for early Alzheimer’s disease therapies is that treatment “must begin before there are overt clinical symptoms.”
“We enthusiastically support this idea,” said Dr. Edelmeyer. “Prevention of Alzheimer’s dementia is possible through changing the course, stopping the progression, and eventually interrupting the causes of the disease, most likely through a combination of lifestyle/behavior choices and pharmaceutical intervention,” she added.
A version of this article appeared on Medscape.com.
Does Abdominal Fat Location Matter for Brain Health?
TOPLINE:
METHODOLOGY:
- Obesity is a well-known risk factor for poorer cognition and dementia, but the distribution of body fat may influence the risk and underlying mechanisms in the fat-brain-cognition pathway.
- The study examined associations of several abdominal fat depots with cognitive functioning and AD-related brain volumes.
- The study sample included 204 men and women from the Israel Registry for Alzheimer’s Prevention (mean age, 59 years; 60% women) who had a high AD risk due to parental family history.
- Abdominal MRI scans assessed fat stored as subcutaneous adipose tissue (SAT) beneath the skin, visceral adipose tissue (VAT) around abdominal organs, and ectopic, a harmful condition in which lipids accumulate in lean tissues such as the liver and pancreas.
- A structural volumetric brain MRI scan was undertaken by 142 participants to assess specific regions implicated in chosen previous research.
TAKEAWAY:
- High body mass index was associated with high pancreatic fat percentage in both men and women (P < .001) and with high SAT percentage in women (P = .01) but not with VAT percentage in either sex.
- After adjustment for cardiovascular risk factors, a higher pancreatic fat percentage was linked to lower global cognition (beta, −0.33; P = .02) and executive function (beta, −0.32; P = .02) in men, and with lower hippocampal volume in women (beta, −0.25; P = .03).
- In men only, a higher SAT percentage was associated with a lower middle frontal gyrus volume (beta, −0.27; P = .03), while a higher VAT percentage was linked to higher middle frontal gyrus (beta, 0.29; P = .03) and superior frontal gyrus volumes (beta, 0.31; P = .02).
- Hepatic fat was not associated with brain volumes or cognition in either men or women.
IN PRACTICE:
“These results suggest that already in midlife, abdominal fat accumulation may have deleterious effects on brain health, especially in men,” the authors wrote.
SOURCE:
This study was led by Sapir G. Shekhtman, Faculty of Medicine, Tel Aviv University, Tel Aviv, Israel, and published online in Obesity (Silver Spring).
LIMITATIONS:
No causal inferences could be drawn from this study due to its cross-sectional nature. It did not represent the population of middle-aged adults as a whole, but rather those at high risk of developing AD. Factors contributing to fat accumulation, such as menopausal status or treatment, inflammation, insulin resistance, daily exercise, and dietary factors, were not included in this study.
DISCLOSURES:
This work was supported by grants from the National Institutes of Health. The authors declared no conflicts of interest.
A version of this article appeared on Medscape.com.
TOPLINE:
METHODOLOGY:
- Obesity is a well-known risk factor for poorer cognition and dementia, but the distribution of body fat may influence the risk and underlying mechanisms in the fat-brain-cognition pathway.
- The study examined associations of several abdominal fat depots with cognitive functioning and AD-related brain volumes.
- The study sample included 204 men and women from the Israel Registry for Alzheimer’s Prevention (mean age, 59 years; 60% women) who had a high AD risk due to parental family history.
- Abdominal MRI scans assessed fat stored as subcutaneous adipose tissue (SAT) beneath the skin, visceral adipose tissue (VAT) around abdominal organs, and ectopic, a harmful condition in which lipids accumulate in lean tissues such as the liver and pancreas.
- A structural volumetric brain MRI scan was undertaken by 142 participants to assess specific regions implicated in chosen previous research.
TAKEAWAY:
- High body mass index was associated with high pancreatic fat percentage in both men and women (P < .001) and with high SAT percentage in women (P = .01) but not with VAT percentage in either sex.
- After adjustment for cardiovascular risk factors, a higher pancreatic fat percentage was linked to lower global cognition (beta, −0.33; P = .02) and executive function (beta, −0.32; P = .02) in men, and with lower hippocampal volume in women (beta, −0.25; P = .03).
- In men only, a higher SAT percentage was associated with a lower middle frontal gyrus volume (beta, −0.27; P = .03), while a higher VAT percentage was linked to higher middle frontal gyrus (beta, 0.29; P = .03) and superior frontal gyrus volumes (beta, 0.31; P = .02).
- Hepatic fat was not associated with brain volumes or cognition in either men or women.
IN PRACTICE:
“These results suggest that already in midlife, abdominal fat accumulation may have deleterious effects on brain health, especially in men,” the authors wrote.
SOURCE:
This study was led by Sapir G. Shekhtman, Faculty of Medicine, Tel Aviv University, Tel Aviv, Israel, and published online in Obesity (Silver Spring).
LIMITATIONS:
No causal inferences could be drawn from this study due to its cross-sectional nature. It did not represent the population of middle-aged adults as a whole, but rather those at high risk of developing AD. Factors contributing to fat accumulation, such as menopausal status or treatment, inflammation, insulin resistance, daily exercise, and dietary factors, were not included in this study.
DISCLOSURES:
This work was supported by grants from the National Institutes of Health. The authors declared no conflicts of interest.
A version of this article appeared on Medscape.com.
TOPLINE:
METHODOLOGY:
- Obesity is a well-known risk factor for poorer cognition and dementia, but the distribution of body fat may influence the risk and underlying mechanisms in the fat-brain-cognition pathway.
- The study examined associations of several abdominal fat depots with cognitive functioning and AD-related brain volumes.
- The study sample included 204 men and women from the Israel Registry for Alzheimer’s Prevention (mean age, 59 years; 60% women) who had a high AD risk due to parental family history.
- Abdominal MRI scans assessed fat stored as subcutaneous adipose tissue (SAT) beneath the skin, visceral adipose tissue (VAT) around abdominal organs, and ectopic, a harmful condition in which lipids accumulate in lean tissues such as the liver and pancreas.
- A structural volumetric brain MRI scan was undertaken by 142 participants to assess specific regions implicated in chosen previous research.
TAKEAWAY:
- High body mass index was associated with high pancreatic fat percentage in both men and women (P < .001) and with high SAT percentage in women (P = .01) but not with VAT percentage in either sex.
- After adjustment for cardiovascular risk factors, a higher pancreatic fat percentage was linked to lower global cognition (beta, −0.33; P = .02) and executive function (beta, −0.32; P = .02) in men, and with lower hippocampal volume in women (beta, −0.25; P = .03).
- In men only, a higher SAT percentage was associated with a lower middle frontal gyrus volume (beta, −0.27; P = .03), while a higher VAT percentage was linked to higher middle frontal gyrus (beta, 0.29; P = .03) and superior frontal gyrus volumes (beta, 0.31; P = .02).
- Hepatic fat was not associated with brain volumes or cognition in either men or women.
IN PRACTICE:
“These results suggest that already in midlife, abdominal fat accumulation may have deleterious effects on brain health, especially in men,” the authors wrote.
SOURCE:
This study was led by Sapir G. Shekhtman, Faculty of Medicine, Tel Aviv University, Tel Aviv, Israel, and published online in Obesity (Silver Spring).
LIMITATIONS:
No causal inferences could be drawn from this study due to its cross-sectional nature. It did not represent the population of middle-aged adults as a whole, but rather those at high risk of developing AD. Factors contributing to fat accumulation, such as menopausal status or treatment, inflammation, insulin resistance, daily exercise, and dietary factors, were not included in this study.
DISCLOSURES:
This work was supported by grants from the National Institutes of Health. The authors declared no conflicts of interest.
A version of this article appeared on Medscape.com.
Neurological Disorders Now Top Global Cause of Illness, Disability
, a new comprehensive analysis showed.
In 2021, neurological conditions were responsible for 443 million years of healthy life lost due to illness, disability, and premature death — a measurement known as disability-adjusted life years (DALY) — making them the top contributor to the global disease burden, ahead of cardiovascular diseases.
Some 3.4 billion people — 43% of the entire global population — had a neurological illness in 2021, the report noted.
“As the world’s leading cause of overall disease burden, and with case numbers rising 59% globally since 1990, nervous system conditions must be addressed through effective, culturally acceptable, and affordable prevention, treatment, rehabilitation, and long-term care strategies,” lead author Jaimie Steinmetz, PhD, from the Institute of Health Metrics and Evaluation (IHME), University of Washington, Seattle, said in a news release.
The findings, from the Global Burden of Disease, Injuries, and Risk Factors Study (GBD) 2021, “have important health service and policy implications and serve as evidence that global neurological heath loss has been under-recognized and is increasing and unevenly distributed geographically and socioeconomically,” the authors noted.
The study was published online in The Lancet: Neurology.
The Top 10
The top 10 contributors to neurological health loss in 2021 were stroke, neonatal encephalopathy, migraine, Alzheimer’s disease and other dementias, diabetic neuropathy, meningitis, epilepsy, neurological complications from preterm birth, autistic spectrum disorders, and nervous system cancers.
Neurological consequences of COVID-19 ranked 20th out of 37 unique conditions assessed.
In 2021, there were more than 23 million global cases of COVID-19 with long-term cognitive symptoms or Guillain-Barré syndrome, accounting for 57% of all infectious neurological disease cases and contributing to 2.48 million years of healthy life lost, the study found.
The most prevalent neurological disorders were tension-type headache (about 2 billion cases) and migraine (about 1.1 billion cases), while diabetic neuropathy is the fastest-growing of all neurological conditions.
“The number of people with diabetic neuropathy has more than tripled globally since 1990, rising to 206 million in 2021. This is in line with the increase in the global prevalence of diabetes,” co-senior author Liane Ong, PhD, from IHME, said in the release.
The data showed striking differences in the burden of neurological conditions between world regions and national income levels, with over 80% of neurological deaths and health loss occurring in low- and middle-income countries.
Regions with the highest burden of neurological conditions were central and western sub-Saharan Africa, while high-income Asia Pacific and Australasia had the lowest burden.
“Nervous system health loss disproportionately impacts many of the poorest countries partly due to the higher prevalence of conditions affecting neonates and children under 5, especially birth-related complications and infections,” co-senior author Tarun Dua, MD, with the World Health Organization (WHO) brain health unit, noted in the news release.
“Improved infant survival has led to an increase in long-term disability, while limited access to treatment and rehabilitation services is contributing to the much higher proportion of deaths in these countries,” Dr. Dua said.
Prioritize Prevention
The analysis also provides estimates of the proportion of neurological conditions that are potentially preventable by eliminating known risk factors for stroke, dementia, multiple sclerosis, Parkinson’s disease, encephalitis, meningitis, and intellectual disability.
It shows that modifying 18 risk factors over a person’s lifetime — most importantly high systolic blood pressure — could prevent 84% of global DALYs from stroke. Controlling lead exposure could lower intellectual disability cases by 63% and reducing high fasting plasma glucose to normal levels could cut dementia by roughly 15%.
“Because many neurological conditions lack cures, and access to medical care is often limited, understanding modifiable risk factors and the potentially avoidable neurological condition burden is essential to help curb this global health crisis,” co-lead author Katrin Seeher, PhD, mental health specialist with WHO’s brain health unit, said in the release.
It’s important to note that nervous system conditions include infectious and vector-borne diseases and injuries as well as noncommunicable diseases and injuries, Dr. Steinmetz said, “demanding different strategies for prevention and treatment throughout life.”
“We hope that our findings can help policymakers more comprehensively understand the impact of neurological conditions on both adults and children to inform more targeted interventions in individual countries, as well as guide ongoing awareness and advocacy efforts around the world,” Dr. Steinmetz added.
In an accompanying editorial, Wolfgang Grisold, MD, president of the World Federation of Neurology, London, noted that the study builds on previous findings and expands the number of neurological conditions studied from 15 to 37.
“This important new GBD report highlights that the burden of neurological conditions is greater than previously thought,” wrote Dr. Grisold, who was not a part of the study. “In the next iteration, more attention should be given to neuromuscular diseases, the effects of cancer in the nervous system, and neuropathic pain. Comparing the disability caused by conditions with episodic occurrence versus those that cause permanent and progressive disease will remain challenging because the effects on the individuals vary substantially.”
The study was funded by the Bill and Melinda Gates Foundation. Full disclosures are included in the original article.
A version of this article appeared on Medscape.com.
, a new comprehensive analysis showed.
In 2021, neurological conditions were responsible for 443 million years of healthy life lost due to illness, disability, and premature death — a measurement known as disability-adjusted life years (DALY) — making them the top contributor to the global disease burden, ahead of cardiovascular diseases.
Some 3.4 billion people — 43% of the entire global population — had a neurological illness in 2021, the report noted.
“As the world’s leading cause of overall disease burden, and with case numbers rising 59% globally since 1990, nervous system conditions must be addressed through effective, culturally acceptable, and affordable prevention, treatment, rehabilitation, and long-term care strategies,” lead author Jaimie Steinmetz, PhD, from the Institute of Health Metrics and Evaluation (IHME), University of Washington, Seattle, said in a news release.
The findings, from the Global Burden of Disease, Injuries, and Risk Factors Study (GBD) 2021, “have important health service and policy implications and serve as evidence that global neurological heath loss has been under-recognized and is increasing and unevenly distributed geographically and socioeconomically,” the authors noted.
The study was published online in The Lancet: Neurology.
The Top 10
The top 10 contributors to neurological health loss in 2021 were stroke, neonatal encephalopathy, migraine, Alzheimer’s disease and other dementias, diabetic neuropathy, meningitis, epilepsy, neurological complications from preterm birth, autistic spectrum disorders, and nervous system cancers.
Neurological consequences of COVID-19 ranked 20th out of 37 unique conditions assessed.
In 2021, there were more than 23 million global cases of COVID-19 with long-term cognitive symptoms or Guillain-Barré syndrome, accounting for 57% of all infectious neurological disease cases and contributing to 2.48 million years of healthy life lost, the study found.
The most prevalent neurological disorders were tension-type headache (about 2 billion cases) and migraine (about 1.1 billion cases), while diabetic neuropathy is the fastest-growing of all neurological conditions.
“The number of people with diabetic neuropathy has more than tripled globally since 1990, rising to 206 million in 2021. This is in line with the increase in the global prevalence of diabetes,” co-senior author Liane Ong, PhD, from IHME, said in the release.
The data showed striking differences in the burden of neurological conditions between world regions and national income levels, with over 80% of neurological deaths and health loss occurring in low- and middle-income countries.
Regions with the highest burden of neurological conditions were central and western sub-Saharan Africa, while high-income Asia Pacific and Australasia had the lowest burden.
“Nervous system health loss disproportionately impacts many of the poorest countries partly due to the higher prevalence of conditions affecting neonates and children under 5, especially birth-related complications and infections,” co-senior author Tarun Dua, MD, with the World Health Organization (WHO) brain health unit, noted in the news release.
“Improved infant survival has led to an increase in long-term disability, while limited access to treatment and rehabilitation services is contributing to the much higher proportion of deaths in these countries,” Dr. Dua said.
Prioritize Prevention
The analysis also provides estimates of the proportion of neurological conditions that are potentially preventable by eliminating known risk factors for stroke, dementia, multiple sclerosis, Parkinson’s disease, encephalitis, meningitis, and intellectual disability.
It shows that modifying 18 risk factors over a person’s lifetime — most importantly high systolic blood pressure — could prevent 84% of global DALYs from stroke. Controlling lead exposure could lower intellectual disability cases by 63% and reducing high fasting plasma glucose to normal levels could cut dementia by roughly 15%.
“Because many neurological conditions lack cures, and access to medical care is often limited, understanding modifiable risk factors and the potentially avoidable neurological condition burden is essential to help curb this global health crisis,” co-lead author Katrin Seeher, PhD, mental health specialist with WHO’s brain health unit, said in the release.
It’s important to note that nervous system conditions include infectious and vector-borne diseases and injuries as well as noncommunicable diseases and injuries, Dr. Steinmetz said, “demanding different strategies for prevention and treatment throughout life.”
“We hope that our findings can help policymakers more comprehensively understand the impact of neurological conditions on both adults and children to inform more targeted interventions in individual countries, as well as guide ongoing awareness and advocacy efforts around the world,” Dr. Steinmetz added.
In an accompanying editorial, Wolfgang Grisold, MD, president of the World Federation of Neurology, London, noted that the study builds on previous findings and expands the number of neurological conditions studied from 15 to 37.
“This important new GBD report highlights that the burden of neurological conditions is greater than previously thought,” wrote Dr. Grisold, who was not a part of the study. “In the next iteration, more attention should be given to neuromuscular diseases, the effects of cancer in the nervous system, and neuropathic pain. Comparing the disability caused by conditions with episodic occurrence versus those that cause permanent and progressive disease will remain challenging because the effects on the individuals vary substantially.”
The study was funded by the Bill and Melinda Gates Foundation. Full disclosures are included in the original article.
A version of this article appeared on Medscape.com.
, a new comprehensive analysis showed.
In 2021, neurological conditions were responsible for 443 million years of healthy life lost due to illness, disability, and premature death — a measurement known as disability-adjusted life years (DALY) — making them the top contributor to the global disease burden, ahead of cardiovascular diseases.
Some 3.4 billion people — 43% of the entire global population — had a neurological illness in 2021, the report noted.
“As the world’s leading cause of overall disease burden, and with case numbers rising 59% globally since 1990, nervous system conditions must be addressed through effective, culturally acceptable, and affordable prevention, treatment, rehabilitation, and long-term care strategies,” lead author Jaimie Steinmetz, PhD, from the Institute of Health Metrics and Evaluation (IHME), University of Washington, Seattle, said in a news release.
The findings, from the Global Burden of Disease, Injuries, and Risk Factors Study (GBD) 2021, “have important health service and policy implications and serve as evidence that global neurological heath loss has been under-recognized and is increasing and unevenly distributed geographically and socioeconomically,” the authors noted.
The study was published online in The Lancet: Neurology.
The Top 10
The top 10 contributors to neurological health loss in 2021 were stroke, neonatal encephalopathy, migraine, Alzheimer’s disease and other dementias, diabetic neuropathy, meningitis, epilepsy, neurological complications from preterm birth, autistic spectrum disorders, and nervous system cancers.
Neurological consequences of COVID-19 ranked 20th out of 37 unique conditions assessed.
In 2021, there were more than 23 million global cases of COVID-19 with long-term cognitive symptoms or Guillain-Barré syndrome, accounting for 57% of all infectious neurological disease cases and contributing to 2.48 million years of healthy life lost, the study found.
The most prevalent neurological disorders were tension-type headache (about 2 billion cases) and migraine (about 1.1 billion cases), while diabetic neuropathy is the fastest-growing of all neurological conditions.
“The number of people with diabetic neuropathy has more than tripled globally since 1990, rising to 206 million in 2021. This is in line with the increase in the global prevalence of diabetes,” co-senior author Liane Ong, PhD, from IHME, said in the release.
The data showed striking differences in the burden of neurological conditions between world regions and national income levels, with over 80% of neurological deaths and health loss occurring in low- and middle-income countries.
Regions with the highest burden of neurological conditions were central and western sub-Saharan Africa, while high-income Asia Pacific and Australasia had the lowest burden.
“Nervous system health loss disproportionately impacts many of the poorest countries partly due to the higher prevalence of conditions affecting neonates and children under 5, especially birth-related complications and infections,” co-senior author Tarun Dua, MD, with the World Health Organization (WHO) brain health unit, noted in the news release.
“Improved infant survival has led to an increase in long-term disability, while limited access to treatment and rehabilitation services is contributing to the much higher proportion of deaths in these countries,” Dr. Dua said.
Prioritize Prevention
The analysis also provides estimates of the proportion of neurological conditions that are potentially preventable by eliminating known risk factors for stroke, dementia, multiple sclerosis, Parkinson’s disease, encephalitis, meningitis, and intellectual disability.
It shows that modifying 18 risk factors over a person’s lifetime — most importantly high systolic blood pressure — could prevent 84% of global DALYs from stroke. Controlling lead exposure could lower intellectual disability cases by 63% and reducing high fasting plasma glucose to normal levels could cut dementia by roughly 15%.
“Because many neurological conditions lack cures, and access to medical care is often limited, understanding modifiable risk factors and the potentially avoidable neurological condition burden is essential to help curb this global health crisis,” co-lead author Katrin Seeher, PhD, mental health specialist with WHO’s brain health unit, said in the release.
It’s important to note that nervous system conditions include infectious and vector-borne diseases and injuries as well as noncommunicable diseases and injuries, Dr. Steinmetz said, “demanding different strategies for prevention and treatment throughout life.”
“We hope that our findings can help policymakers more comprehensively understand the impact of neurological conditions on both adults and children to inform more targeted interventions in individual countries, as well as guide ongoing awareness and advocacy efforts around the world,” Dr. Steinmetz added.
In an accompanying editorial, Wolfgang Grisold, MD, president of the World Federation of Neurology, London, noted that the study builds on previous findings and expands the number of neurological conditions studied from 15 to 37.
“This important new GBD report highlights that the burden of neurological conditions is greater than previously thought,” wrote Dr. Grisold, who was not a part of the study. “In the next iteration, more attention should be given to neuromuscular diseases, the effects of cancer in the nervous system, and neuropathic pain. Comparing the disability caused by conditions with episodic occurrence versus those that cause permanent and progressive disease will remain challenging because the effects on the individuals vary substantially.”
The study was funded by the Bill and Melinda Gates Foundation. Full disclosures are included in the original article.
A version of this article appeared on Medscape.com.
FROM THE LANCET NEUROLOGY
Essential Tremor Tied to a Threefold Increased Risk for Dementia
, new research showed.
In a prospective, longitudinal study, incidence of dementia was nearly 20% among older adults with ET. However, the rates were lower than those in adults with Parkinson’s disease.
The study is “the most complete exposition of the longitudinal trajectory of cognitive impairment in an ET cohort,” said the authors, led by Elan D. Louis, MD, MSc, from University of Texas Southwestern Medical Center in Dallas, Texas.
The findings were released ahead of the study’s scheduled presentation at the annual meeting of the American Academy of Neurology.
Mild Cognitive Impairment Prevalence Nearly Double
For the study, 222 adults with ET with an average age of 79 years at baseline underwent detailed cognitive assessments and were followed for an average of 5 years.
At baseline, 168 people had normal cognitive skills, 35 had mild cognitive impairment (MCI), and 19 had dementia. During the follow-up, 59 individuals developed MCI and 41 developed dementia.
During the follow-up, the cumulative prevalence of dementia was 18.5%, and the average annual conversion rate of MCI to dementia was 12.2% — nearly threefold higher than rates in the general population and roughly one-half the magnitude of those reported for adults with Parkinson’s disease.
The cumulative prevalence of MCI (26.6%) was nearly double that of the general population but less than that in patients with Parkinson’s disease.
“Our data indicate that the prevalence of and conversion rates to dementia in ET fall between those associated with the natural course of aging and the more pronounced rates observed in individuals with Parkinson’s disease,” the researchers wrote in their conference abstract.
Far From Trivial
Reached for comment, Shaheen Lakhan, MD, a neurologist and researcher based in Miami, Florida, said, “The days of viewing ET as just a ‘nuisance tremor’ are over. This study shatters the notion that essential tremor is a trivial condition.”
“Moving forward, the research agenda must further elucidate the link between ET and dementia and develop neuroprotective strategies. But this study represents a seismic shift in how we understand essential tremor,” Dr. Lakhan said.
“The benign label no longer applies given the cognitive risks ET patients face. Our clinical practice and communication with patients must adapt accordingly,” he added.
The study was supported by the National Institutes of Health. Drs. Louis and Lakhan had no relevant disclosures.
A version of this article appeared on Medscape.com.
, new research showed.
In a prospective, longitudinal study, incidence of dementia was nearly 20% among older adults with ET. However, the rates were lower than those in adults with Parkinson’s disease.
The study is “the most complete exposition of the longitudinal trajectory of cognitive impairment in an ET cohort,” said the authors, led by Elan D. Louis, MD, MSc, from University of Texas Southwestern Medical Center in Dallas, Texas.
The findings were released ahead of the study’s scheduled presentation at the annual meeting of the American Academy of Neurology.
Mild Cognitive Impairment Prevalence Nearly Double
For the study, 222 adults with ET with an average age of 79 years at baseline underwent detailed cognitive assessments and were followed for an average of 5 years.
At baseline, 168 people had normal cognitive skills, 35 had mild cognitive impairment (MCI), and 19 had dementia. During the follow-up, 59 individuals developed MCI and 41 developed dementia.
During the follow-up, the cumulative prevalence of dementia was 18.5%, and the average annual conversion rate of MCI to dementia was 12.2% — nearly threefold higher than rates in the general population and roughly one-half the magnitude of those reported for adults with Parkinson’s disease.
The cumulative prevalence of MCI (26.6%) was nearly double that of the general population but less than that in patients with Parkinson’s disease.
“Our data indicate that the prevalence of and conversion rates to dementia in ET fall between those associated with the natural course of aging and the more pronounced rates observed in individuals with Parkinson’s disease,” the researchers wrote in their conference abstract.
Far From Trivial
Reached for comment, Shaheen Lakhan, MD, a neurologist and researcher based in Miami, Florida, said, “The days of viewing ET as just a ‘nuisance tremor’ are over. This study shatters the notion that essential tremor is a trivial condition.”
“Moving forward, the research agenda must further elucidate the link between ET and dementia and develop neuroprotective strategies. But this study represents a seismic shift in how we understand essential tremor,” Dr. Lakhan said.
“The benign label no longer applies given the cognitive risks ET patients face. Our clinical practice and communication with patients must adapt accordingly,” he added.
The study was supported by the National Institutes of Health. Drs. Louis and Lakhan had no relevant disclosures.
A version of this article appeared on Medscape.com.
, new research showed.
In a prospective, longitudinal study, incidence of dementia was nearly 20% among older adults with ET. However, the rates were lower than those in adults with Parkinson’s disease.
The study is “the most complete exposition of the longitudinal trajectory of cognitive impairment in an ET cohort,” said the authors, led by Elan D. Louis, MD, MSc, from University of Texas Southwestern Medical Center in Dallas, Texas.
The findings were released ahead of the study’s scheduled presentation at the annual meeting of the American Academy of Neurology.
Mild Cognitive Impairment Prevalence Nearly Double
For the study, 222 adults with ET with an average age of 79 years at baseline underwent detailed cognitive assessments and were followed for an average of 5 years.
At baseline, 168 people had normal cognitive skills, 35 had mild cognitive impairment (MCI), and 19 had dementia. During the follow-up, 59 individuals developed MCI and 41 developed dementia.
During the follow-up, the cumulative prevalence of dementia was 18.5%, and the average annual conversion rate of MCI to dementia was 12.2% — nearly threefold higher than rates in the general population and roughly one-half the magnitude of those reported for adults with Parkinson’s disease.
The cumulative prevalence of MCI (26.6%) was nearly double that of the general population but less than that in patients with Parkinson’s disease.
“Our data indicate that the prevalence of and conversion rates to dementia in ET fall between those associated with the natural course of aging and the more pronounced rates observed in individuals with Parkinson’s disease,” the researchers wrote in their conference abstract.
Far From Trivial
Reached for comment, Shaheen Lakhan, MD, a neurologist and researcher based in Miami, Florida, said, “The days of viewing ET as just a ‘nuisance tremor’ are over. This study shatters the notion that essential tremor is a trivial condition.”
“Moving forward, the research agenda must further elucidate the link between ET and dementia and develop neuroprotective strategies. But this study represents a seismic shift in how we understand essential tremor,” Dr. Lakhan said.
“The benign label no longer applies given the cognitive risks ET patients face. Our clinical practice and communication with patients must adapt accordingly,” he added.
The study was supported by the National Institutes of Health. Drs. Louis and Lakhan had no relevant disclosures.
A version of this article appeared on Medscape.com.
FROM AAN 2024
Alzheimer’s Research Has an Integrity Problem, Claim Investigators
The book is yet to be closed, for instance, on whether a 2006 paper by Sylvain Lesne positing amyloid as a major cause of Alzheimer’s was based on fraudulent data. Suspicions about the paper were first raised in late 2021 by Matthew Schrag, MD, PhD, an assistant professor of neurology at Vanderbilt University Medical Center, Nashville, Tennessee.
Dr. Schrag also queried the work of a City University of New York (CUNY) researcher who proposed PT-125 (now simufilam) as a potential anti-amyloid for Alzheimer’s disease. Even though CUNY recently found “egregious” and potentially deliberate misconduct by that researcher, Cassava Sciences is continuing phase 3 trials of simufilam.
Now questions are being raised about work from the lab of Berislav V. Zlokovic, PhD, a prominent neuroscientist at the University of Southern California (USC), Los Angeles, California, and also about studies conducted under the aegis of Domenico Pratico, MD, the director of the Alzheimer’s Center at Temple University in Philadelphia, Pennsylvania.
Alzheimer’s has been a notoriously hard puzzle to solve. Despite decades of research, there are still no effective therapies and disparate theories about potential causes.
Dr. Schrag said he wouldn’t “attribute all the ills in this field” to misconduct, but it “is absolutely a part of the equation.” Some of the papers flagged for integrity issues “have been hugely influential,” he said in an interview. “Some of the labs that we’re talking about have really shaped how we’ve thought about this disease,” he said. “It’s hard to un-ring the bell.”
The fallout from fraud has a wide impact. Taxpayer dollars are wasted in the creation of the fraud and in attempts to replicate the failed experiment. Grad students — the workhorses of labs — waste time trying to repeat studies or may be bullied or intimidated into misconduct, said Elisabeth Bik, PhD, a former Stanford microbiologist who is now a full-time fraud investigator.
And there’s potential harm to patients. “There’s a lot of false hope being given to these people and their families,” Dr. Bik said in an interview.
Alzheimer’s Tempts With Big Rewards
There are big rewards for those who publish important papers on Alzheimer’s: More grants, publication in higher-impact journals, larger labs, and potentially, personal enrichment from commercialization of therapies.
“I can see that people are driven to cut corners or even to make up results, or even anything in between, to reach that goal,” said Dr. Bik.
It’s unclear whether misconduct and fraud are on the rise or just being detected more frequently.
“It’s very hard to say,” said Mike Rossner, PhD, president of Image Data Integrity. Institutions hire Dr. Rossner to help ferret out research integrity issues. He told this news organization that it’s likely detection is on the rise, given the increasing number of sleuths like Dr. Bik.
In 2002, Dr. Rossner began to screen all images submitted to the Journal of Clinical Biology in response to the new phenomenon of digital images and the advent of PhotoShop. “Very early on, we started to see problems in digital images that we would not have seen on a glossy printout,” Dr. Rossner said of his time as managing editor of the journal.
From 2002 to 2014, at least 25% of papers had an image that violated guidelines that prohibited the removal of spots or other blemishes (called “beautification”) with PhotoShop, which did not necessarily indicate fraud. They withdrew acceptance for 1% of papers because of image manipulations that affected data interpretation.
Dr. Bik noted that even if there is not a greater percentage of fraudulent papers in Alzheimer’s, “it would still be in absolute numbers a lot of papers that could be fraudulent,” given that Alzheimer’s research is well-funded with federal agencies alone providing $3.7 billion a year.
Images Key to Spotting Issues
Investigative sleuths often use the online forum PubPeer to initially raise questions about papers. The format gives the original authors a chance to comment on or defend their work. While some critiques are about data, most hone in on alleged duplications or manipulations of images, primarily by Western Blots.
The images are key, because “the images are the data,” said Dr. Rossner. “The words are the author’s interpretation of what they see in the images,” he said.
It’s also easier to spot a problem in an image. The raw data or an investigator’s notebooks aren’t needed, and there are artificial intelligence-driven software programs such as Proofig and Image Twin that help investigators spot duplicated images or cases in which an image might have been flipped or otherwise manipulated to make results look better.
Science recently announced that it would be using Proofig to screen images in all papers submitted to its six journals.
Using a screening tool is better than nothing, said Dr. Rossner who still relies on visual inspection, employing contrast or other features in PhotoShop to spot inconsistencies or duplications. But “none of those companies have disclosed how effective they are relative to visual screening, and that to me is very problematic,” he said.
“The tools are not going to catch everything,” said Dr. Bik.
Dr. Schrag agreed. “One of the things that we’re worried about is that a lot of the journals will simply adopt these tools as a screener and assume that that’s going to de-risk their publication portfolio,” he said, noting the high rate of misses.
Artificial Intelligence a Growing Concern
Artificial intelligence (AI) may also accelerate the amount of fraud and add to the difficulty of ferreting it out, said the investigators.
“I’m very worried about AI,” said Dr. Bik. Although AI-generated images and content may be rudimentary today, “next year it’s going to be much better,” she said. Going forward, it may be hard to distinguish between a real dataset and one that has been generated by AI, she said.
“The more closely AI can mimic authentic content, the more difficult it will be for publications to detect intentionally fraudulent submissions,” wrote Dror Kolodkin-Gal, PhD, the founder of Proofig, in an article for the Council of Science Editors.
Dr. Kolodkin-Gal said that AI may be especially prone to misuse by paper mills. Those operations submit fake or shoddy manuscripts to a journal on behalf of researchers seeking publication who pay the mills a fee. The Committee on Publication Ethics reported in 2022 that 2%-46% of papers submitted to journals may be from paper mills.
While it’s unclear whether AI is having any impact now, Dr. Rossner said, “I think I can be pretty confident in saying it is going to be a growing problem” as the tools become more sophisticated.
He sees parallels with the rise of PhotoShop and cites data from the National Institute of Health’s Office of Research Integrity (ORI) showing that in 1990, when PhotoShop was still new, 2% of cases referred to ORI involved image manipulation. By 2007, 70% of cases had image manipulation issues.
Journals, Institutions Need to Step Up More
Fraud may continue apace in part because investigations drag on for years, and in many cases, with a lack of consequences for the perpetrators, said the investigators. And, they say, journals and institutions haven’t devoted enough resources to prevent or investigate misconduct.
“A lot of editors did not even want to investigate because they just didn’t want to believe that there could be fraud in science,” said Dr. Bik of her experiences. “I hope that by now most journals at least should have realized that some proportion of the manuscripts that get sent to their journals is going to be fraud,” she said.
“The bulk of the journals seem like they don’t want to be bothered by this,” agreed Dr. Schrag, adding that “some have gone to great lengths to try to discourage people from bringing forward complaints.”
A big issue is that journals “don’t answer to any higher authority,” said Dr. Schrag. He believes that journals that repeatedly refuse to address integrity issues should be barred from publishing research produced with funds from the National Institutes of Health.
All the investigators said institutions and journals should hire forensic investigators. Relying on unpaid peer reviewers or editors to root out fraud is unrealistic, they said.
“You want to have specialized people with experience and be paid to do that as a full-time job,” said Dr. Bik, who is funded by speaking engagements and receives about $2300 a month through donations to her Patreon account.
Once a potential integrity issue is flagged, there is “an incredible conflict of interest in how these investigations are run,” said Dr. Schrag. “Institutions are asked to investigate their own faculty; they’re asked to investigate themselves.” That “creates the disincentive to move expeditiously,” said Dr. Schrag.
With the space of time, people who have committed fraud can throw out notebooks, delete data from servers, or even PhotoShop original photos so they match the manipulated ones that were submitted, Dr. Bik said.
Institutions could show they are serious about fraud by offering a “central, systematic universal screening of all image data going out of their institutions before submission to a journal,” said Dr. Rossner. But he knows only of a handful that do so. “I think research integrity offices have historically been very reactive, and they need to pivot and become proactive,” said Dr. Rossner.
Dr. Schrag wants to see stronger values within the research enterprise. “You have to build a culture where it’s absolutely anathema at a core level to violate these standards of research integrity,” he said. “We have this notion that we can push the process along faster and get to a grant and get to a paper and get to some short-term goal,” he said. “But the long-term goal in most of these cases is to cure a disease or to understand some biological mysteries. There’s no shortcut to getting there,” said Dr. Schrag.
There have been some high-profile consequences for research integrity failures, such as the 2023 resignation of Stanford University President Marc Tessier-Lavigne in the wake of findings that members of his lab — but not Tessier-Lavigne — engaged in data manipulation.
The process is often opaque, with investigations done in secrecy. “Consequences are not usually revealed, either,” said Dr. Rossner.
Dr. Schrag acknowledges it’s a tough balancing act for institutions to root out bad actors while also ensuring there’s no harm to those who may simply have operated in error.
“But it doesn’t serve anyone’s interest including the people who are accused, in dragging these things out for 5, 6, 8, or 10 years,” he said.
Lesne and Cassava: The Long and Winding Road
The investigations into the Lesne papers and the work underpinning Cassava Sciences’ therapy point to the difficulty of policing integrity and the potential fallout.
Lesne’s signature paper published in Nature in 2006 has been cited some 2300 times and is the fourth most-accessed article of 81,612 articles of a similar age in all journals tracked by Altimetrics.
Dr. Schrag, Dr. Bik, and others wrote to multiple journals asking them to investigate some 25 papers related to simufilam, including a 2012 Journal of Clinical Investigation article by Hoau-Yan Wang, PhD, the CUNY scientist whose work on simufilam has been questioned.
JCI Editor Elizabeth McNally pushed back stating in an editorial in 2022 that they, as whistleblowers, had potential conflicts and that they could be assisting short sellers who were seeking to profit by depressing Cassava’s stock price. Indeed, Dr. Schrag was initially hired by a law firm that was representing short sellers. Ms. McNally said that JCI would start requiring disclosures by whistleblowers.
Dr. Bik urged CUNY to investigate Dr. Wang in 2021 but was rebuffed. Then, in November 2023, a copy of CUNY’s final report on the Wang inquiry was leaked to Science. The university reported that Dr. Wang did not provide any original data or notebooks and that it found “long-standing and egregious misconduct in data management and record keeping by Dr. Wang,” wrote Dr. Bik in a blog post summarizing the investigation.
As of late 2023, 42 papers by Dr. Wang have earned PubPeer posts, seven have been retracted, and five have been marked with an Expression of Concern, wrote Dr. Bik.
Some have called for Cassava to stop its phase 3 studies of simufilam, but the company is proceeding, announcing in November 2023 that they have completed enrollment.
Misconduct Queries Underway at USC and Temple
Meanwhile, Dr. Schrag and Dr. Bik continue sleuthing. They are among a small group of whistleblowers who have filed a complaint with NIH about irregularities in the Zlokovic lab at USC. They allege that images were manipulated in dozens of papers, including some that inform the development of a stroke drug in phase 2 trials.
The inquiry goes well beyond stroke, said Dr. Schrag. Dr. Zlokovic “is one of the most influential scientists on Alzheimer’s scientists in the country,” Dr. Schrag said. The USC scientist is a leader on blood-brain barrier research.
USC is investigating “at some level,” he said. In a statement to this news organization, USC said that it “takes any allegations about research integrity very seriously.” The statement added, “Consistent with federal regulations and USC policies, this review must be kept confidential. As a result, we are unable to provide any further information.”
Mu Yang, PhD, assistant professor of neurobiology at Columbia University Medical Center in New York City, is also working on the Zlokovic investigation.
She calls herself an “accidental sleuth” who fell into the hobby after a graduate student asked her to help replicate a study by Temple University, Philadelphia, Pennsylvania, researcher Dominco Pratico, MD, of Alzheimer’s-like phenotype mice in the Morris Water Maze test. Dr. Yang, who runs the “behavior core” at Columbia — teaching and advising on how to run assays and collect and report data — could see right away that the Pratico data were “too perfect.”
She enlisted maze inventor Richard Morris to join her in a letter of concern to the journals that published Dr. Pratico’s work, all under the aegis of Springer Nature.
The publisher’s integrity team has since retracted four Pratico papers. Three were because of image abnormalities pointed out by Dr. Bik, who worked with Dr. Yang. One was because of “self-plagiarism.”
“The official retraction notes didn’t mention anything about data abnormality being a concern,” said Dr. Yang who says that questionable data is harder to prove than an image duplication or manipulation. And the papers remain available, although dozens of Practico papers have been flagged on PubPeer.
To Dr. Yang, images are the canary in the coalmine. “People don’t just fake western blots but then give real behavior data or give you fake behavior data but give you the most authentic Western Blots,” she said.
Dr. Pratico has now sued a graduate student who was a coauthor on the papers, according to the Philadelphia Inquirer.
The NIH’s ORI has requested that Temple University conduct an investigation, Dr. Yang said.
In a statement to this news organization, Temple said it “does not comment on internal investigations or personnel issues,” but that “allegations of research misconduct are reviewed and investigated centrally through Temple’s Office of the Vice President for Research in accordance with university policy and applicable federal regulations.”
A version of this article appeared on Medscape.com.
The book is yet to be closed, for instance, on whether a 2006 paper by Sylvain Lesne positing amyloid as a major cause of Alzheimer’s was based on fraudulent data. Suspicions about the paper were first raised in late 2021 by Matthew Schrag, MD, PhD, an assistant professor of neurology at Vanderbilt University Medical Center, Nashville, Tennessee.
Dr. Schrag also queried the work of a City University of New York (CUNY) researcher who proposed PT-125 (now simufilam) as a potential anti-amyloid for Alzheimer’s disease. Even though CUNY recently found “egregious” and potentially deliberate misconduct by that researcher, Cassava Sciences is continuing phase 3 trials of simufilam.
Now questions are being raised about work from the lab of Berislav V. Zlokovic, PhD, a prominent neuroscientist at the University of Southern California (USC), Los Angeles, California, and also about studies conducted under the aegis of Domenico Pratico, MD, the director of the Alzheimer’s Center at Temple University in Philadelphia, Pennsylvania.
Alzheimer’s has been a notoriously hard puzzle to solve. Despite decades of research, there are still no effective therapies and disparate theories about potential causes.
Dr. Schrag said he wouldn’t “attribute all the ills in this field” to misconduct, but it “is absolutely a part of the equation.” Some of the papers flagged for integrity issues “have been hugely influential,” he said in an interview. “Some of the labs that we’re talking about have really shaped how we’ve thought about this disease,” he said. “It’s hard to un-ring the bell.”
The fallout from fraud has a wide impact. Taxpayer dollars are wasted in the creation of the fraud and in attempts to replicate the failed experiment. Grad students — the workhorses of labs — waste time trying to repeat studies or may be bullied or intimidated into misconduct, said Elisabeth Bik, PhD, a former Stanford microbiologist who is now a full-time fraud investigator.
And there’s potential harm to patients. “There’s a lot of false hope being given to these people and their families,” Dr. Bik said in an interview.
Alzheimer’s Tempts With Big Rewards
There are big rewards for those who publish important papers on Alzheimer’s: More grants, publication in higher-impact journals, larger labs, and potentially, personal enrichment from commercialization of therapies.
“I can see that people are driven to cut corners or even to make up results, or even anything in between, to reach that goal,” said Dr. Bik.
It’s unclear whether misconduct and fraud are on the rise or just being detected more frequently.
“It’s very hard to say,” said Mike Rossner, PhD, president of Image Data Integrity. Institutions hire Dr. Rossner to help ferret out research integrity issues. He told this news organization that it’s likely detection is on the rise, given the increasing number of sleuths like Dr. Bik.
In 2002, Dr. Rossner began to screen all images submitted to the Journal of Clinical Biology in response to the new phenomenon of digital images and the advent of PhotoShop. “Very early on, we started to see problems in digital images that we would not have seen on a glossy printout,” Dr. Rossner said of his time as managing editor of the journal.
From 2002 to 2014, at least 25% of papers had an image that violated guidelines that prohibited the removal of spots or other blemishes (called “beautification”) with PhotoShop, which did not necessarily indicate fraud. They withdrew acceptance for 1% of papers because of image manipulations that affected data interpretation.
Dr. Bik noted that even if there is not a greater percentage of fraudulent papers in Alzheimer’s, “it would still be in absolute numbers a lot of papers that could be fraudulent,” given that Alzheimer’s research is well-funded with federal agencies alone providing $3.7 billion a year.
Images Key to Spotting Issues
Investigative sleuths often use the online forum PubPeer to initially raise questions about papers. The format gives the original authors a chance to comment on or defend their work. While some critiques are about data, most hone in on alleged duplications or manipulations of images, primarily by Western Blots.
The images are key, because “the images are the data,” said Dr. Rossner. “The words are the author’s interpretation of what they see in the images,” he said.
It’s also easier to spot a problem in an image. The raw data or an investigator’s notebooks aren’t needed, and there are artificial intelligence-driven software programs such as Proofig and Image Twin that help investigators spot duplicated images or cases in which an image might have been flipped or otherwise manipulated to make results look better.
Science recently announced that it would be using Proofig to screen images in all papers submitted to its six journals.
Using a screening tool is better than nothing, said Dr. Rossner who still relies on visual inspection, employing contrast or other features in PhotoShop to spot inconsistencies or duplications. But “none of those companies have disclosed how effective they are relative to visual screening, and that to me is very problematic,” he said.
“The tools are not going to catch everything,” said Dr. Bik.
Dr. Schrag agreed. “One of the things that we’re worried about is that a lot of the journals will simply adopt these tools as a screener and assume that that’s going to de-risk their publication portfolio,” he said, noting the high rate of misses.
Artificial Intelligence a Growing Concern
Artificial intelligence (AI) may also accelerate the amount of fraud and add to the difficulty of ferreting it out, said the investigators.
“I’m very worried about AI,” said Dr. Bik. Although AI-generated images and content may be rudimentary today, “next year it’s going to be much better,” she said. Going forward, it may be hard to distinguish between a real dataset and one that has been generated by AI, she said.
“The more closely AI can mimic authentic content, the more difficult it will be for publications to detect intentionally fraudulent submissions,” wrote Dror Kolodkin-Gal, PhD, the founder of Proofig, in an article for the Council of Science Editors.
Dr. Kolodkin-Gal said that AI may be especially prone to misuse by paper mills. Those operations submit fake or shoddy manuscripts to a journal on behalf of researchers seeking publication who pay the mills a fee. The Committee on Publication Ethics reported in 2022 that 2%-46% of papers submitted to journals may be from paper mills.
While it’s unclear whether AI is having any impact now, Dr. Rossner said, “I think I can be pretty confident in saying it is going to be a growing problem” as the tools become more sophisticated.
He sees parallels with the rise of PhotoShop and cites data from the National Institute of Health’s Office of Research Integrity (ORI) showing that in 1990, when PhotoShop was still new, 2% of cases referred to ORI involved image manipulation. By 2007, 70% of cases had image manipulation issues.
Journals, Institutions Need to Step Up More
Fraud may continue apace in part because investigations drag on for years, and in many cases, with a lack of consequences for the perpetrators, said the investigators. And, they say, journals and institutions haven’t devoted enough resources to prevent or investigate misconduct.
“A lot of editors did not even want to investigate because they just didn’t want to believe that there could be fraud in science,” said Dr. Bik of her experiences. “I hope that by now most journals at least should have realized that some proportion of the manuscripts that get sent to their journals is going to be fraud,” she said.
“The bulk of the journals seem like they don’t want to be bothered by this,” agreed Dr. Schrag, adding that “some have gone to great lengths to try to discourage people from bringing forward complaints.”
A big issue is that journals “don’t answer to any higher authority,” said Dr. Schrag. He believes that journals that repeatedly refuse to address integrity issues should be barred from publishing research produced with funds from the National Institutes of Health.
All the investigators said institutions and journals should hire forensic investigators. Relying on unpaid peer reviewers or editors to root out fraud is unrealistic, they said.
“You want to have specialized people with experience and be paid to do that as a full-time job,” said Dr. Bik, who is funded by speaking engagements and receives about $2300 a month through donations to her Patreon account.
Once a potential integrity issue is flagged, there is “an incredible conflict of interest in how these investigations are run,” said Dr. Schrag. “Institutions are asked to investigate their own faculty; they’re asked to investigate themselves.” That “creates the disincentive to move expeditiously,” said Dr. Schrag.
With the space of time, people who have committed fraud can throw out notebooks, delete data from servers, or even PhotoShop original photos so they match the manipulated ones that were submitted, Dr. Bik said.
Institutions could show they are serious about fraud by offering a “central, systematic universal screening of all image data going out of their institutions before submission to a journal,” said Dr. Rossner. But he knows only of a handful that do so. “I think research integrity offices have historically been very reactive, and they need to pivot and become proactive,” said Dr. Rossner.
Dr. Schrag wants to see stronger values within the research enterprise. “You have to build a culture where it’s absolutely anathema at a core level to violate these standards of research integrity,” he said. “We have this notion that we can push the process along faster and get to a grant and get to a paper and get to some short-term goal,” he said. “But the long-term goal in most of these cases is to cure a disease or to understand some biological mysteries. There’s no shortcut to getting there,” said Dr. Schrag.
There have been some high-profile consequences for research integrity failures, such as the 2023 resignation of Stanford University President Marc Tessier-Lavigne in the wake of findings that members of his lab — but not Tessier-Lavigne — engaged in data manipulation.
The process is often opaque, with investigations done in secrecy. “Consequences are not usually revealed, either,” said Dr. Rossner.
Dr. Schrag acknowledges it’s a tough balancing act for institutions to root out bad actors while also ensuring there’s no harm to those who may simply have operated in error.
“But it doesn’t serve anyone’s interest including the people who are accused, in dragging these things out for 5, 6, 8, or 10 years,” he said.
Lesne and Cassava: The Long and Winding Road
The investigations into the Lesne papers and the work underpinning Cassava Sciences’ therapy point to the difficulty of policing integrity and the potential fallout.
Lesne’s signature paper published in Nature in 2006 has been cited some 2300 times and is the fourth most-accessed article of 81,612 articles of a similar age in all journals tracked by Altimetrics.
Dr. Schrag, Dr. Bik, and others wrote to multiple journals asking them to investigate some 25 papers related to simufilam, including a 2012 Journal of Clinical Investigation article by Hoau-Yan Wang, PhD, the CUNY scientist whose work on simufilam has been questioned.
JCI Editor Elizabeth McNally pushed back stating in an editorial in 2022 that they, as whistleblowers, had potential conflicts and that they could be assisting short sellers who were seeking to profit by depressing Cassava’s stock price. Indeed, Dr. Schrag was initially hired by a law firm that was representing short sellers. Ms. McNally said that JCI would start requiring disclosures by whistleblowers.
Dr. Bik urged CUNY to investigate Dr. Wang in 2021 but was rebuffed. Then, in November 2023, a copy of CUNY’s final report on the Wang inquiry was leaked to Science. The university reported that Dr. Wang did not provide any original data or notebooks and that it found “long-standing and egregious misconduct in data management and record keeping by Dr. Wang,” wrote Dr. Bik in a blog post summarizing the investigation.
As of late 2023, 42 papers by Dr. Wang have earned PubPeer posts, seven have been retracted, and five have been marked with an Expression of Concern, wrote Dr. Bik.
Some have called for Cassava to stop its phase 3 studies of simufilam, but the company is proceeding, announcing in November 2023 that they have completed enrollment.
Misconduct Queries Underway at USC and Temple
Meanwhile, Dr. Schrag and Dr. Bik continue sleuthing. They are among a small group of whistleblowers who have filed a complaint with NIH about irregularities in the Zlokovic lab at USC. They allege that images were manipulated in dozens of papers, including some that inform the development of a stroke drug in phase 2 trials.
The inquiry goes well beyond stroke, said Dr. Schrag. Dr. Zlokovic “is one of the most influential scientists on Alzheimer’s scientists in the country,” Dr. Schrag said. The USC scientist is a leader on blood-brain barrier research.
USC is investigating “at some level,” he said. In a statement to this news organization, USC said that it “takes any allegations about research integrity very seriously.” The statement added, “Consistent with federal regulations and USC policies, this review must be kept confidential. As a result, we are unable to provide any further information.”
Mu Yang, PhD, assistant professor of neurobiology at Columbia University Medical Center in New York City, is also working on the Zlokovic investigation.
She calls herself an “accidental sleuth” who fell into the hobby after a graduate student asked her to help replicate a study by Temple University, Philadelphia, Pennsylvania, researcher Dominco Pratico, MD, of Alzheimer’s-like phenotype mice in the Morris Water Maze test. Dr. Yang, who runs the “behavior core” at Columbia — teaching and advising on how to run assays and collect and report data — could see right away that the Pratico data were “too perfect.”
She enlisted maze inventor Richard Morris to join her in a letter of concern to the journals that published Dr. Pratico’s work, all under the aegis of Springer Nature.
The publisher’s integrity team has since retracted four Pratico papers. Three were because of image abnormalities pointed out by Dr. Bik, who worked with Dr. Yang. One was because of “self-plagiarism.”
“The official retraction notes didn’t mention anything about data abnormality being a concern,” said Dr. Yang who says that questionable data is harder to prove than an image duplication or manipulation. And the papers remain available, although dozens of Practico papers have been flagged on PubPeer.
To Dr. Yang, images are the canary in the coalmine. “People don’t just fake western blots but then give real behavior data or give you fake behavior data but give you the most authentic Western Blots,” she said.
Dr. Pratico has now sued a graduate student who was a coauthor on the papers, according to the Philadelphia Inquirer.
The NIH’s ORI has requested that Temple University conduct an investigation, Dr. Yang said.
In a statement to this news organization, Temple said it “does not comment on internal investigations or personnel issues,” but that “allegations of research misconduct are reviewed and investigated centrally through Temple’s Office of the Vice President for Research in accordance with university policy and applicable federal regulations.”
A version of this article appeared on Medscape.com.
The book is yet to be closed, for instance, on whether a 2006 paper by Sylvain Lesne positing amyloid as a major cause of Alzheimer’s was based on fraudulent data. Suspicions about the paper were first raised in late 2021 by Matthew Schrag, MD, PhD, an assistant professor of neurology at Vanderbilt University Medical Center, Nashville, Tennessee.
Dr. Schrag also queried the work of a City University of New York (CUNY) researcher who proposed PT-125 (now simufilam) as a potential anti-amyloid for Alzheimer’s disease. Even though CUNY recently found “egregious” and potentially deliberate misconduct by that researcher, Cassava Sciences is continuing phase 3 trials of simufilam.
Now questions are being raised about work from the lab of Berislav V. Zlokovic, PhD, a prominent neuroscientist at the University of Southern California (USC), Los Angeles, California, and also about studies conducted under the aegis of Domenico Pratico, MD, the director of the Alzheimer’s Center at Temple University in Philadelphia, Pennsylvania.
Alzheimer’s has been a notoriously hard puzzle to solve. Despite decades of research, there are still no effective therapies and disparate theories about potential causes.
Dr. Schrag said he wouldn’t “attribute all the ills in this field” to misconduct, but it “is absolutely a part of the equation.” Some of the papers flagged for integrity issues “have been hugely influential,” he said in an interview. “Some of the labs that we’re talking about have really shaped how we’ve thought about this disease,” he said. “It’s hard to un-ring the bell.”
The fallout from fraud has a wide impact. Taxpayer dollars are wasted in the creation of the fraud and in attempts to replicate the failed experiment. Grad students — the workhorses of labs — waste time trying to repeat studies or may be bullied or intimidated into misconduct, said Elisabeth Bik, PhD, a former Stanford microbiologist who is now a full-time fraud investigator.
And there’s potential harm to patients. “There’s a lot of false hope being given to these people and their families,” Dr. Bik said in an interview.
Alzheimer’s Tempts With Big Rewards
There are big rewards for those who publish important papers on Alzheimer’s: More grants, publication in higher-impact journals, larger labs, and potentially, personal enrichment from commercialization of therapies.
“I can see that people are driven to cut corners or even to make up results, or even anything in between, to reach that goal,” said Dr. Bik.
It’s unclear whether misconduct and fraud are on the rise or just being detected more frequently.
“It’s very hard to say,” said Mike Rossner, PhD, president of Image Data Integrity. Institutions hire Dr. Rossner to help ferret out research integrity issues. He told this news organization that it’s likely detection is on the rise, given the increasing number of sleuths like Dr. Bik.
In 2002, Dr. Rossner began to screen all images submitted to the Journal of Clinical Biology in response to the new phenomenon of digital images and the advent of PhotoShop. “Very early on, we started to see problems in digital images that we would not have seen on a glossy printout,” Dr. Rossner said of his time as managing editor of the journal.
From 2002 to 2014, at least 25% of papers had an image that violated guidelines that prohibited the removal of spots or other blemishes (called “beautification”) with PhotoShop, which did not necessarily indicate fraud. They withdrew acceptance for 1% of papers because of image manipulations that affected data interpretation.
Dr. Bik noted that even if there is not a greater percentage of fraudulent papers in Alzheimer’s, “it would still be in absolute numbers a lot of papers that could be fraudulent,” given that Alzheimer’s research is well-funded with federal agencies alone providing $3.7 billion a year.
Images Key to Spotting Issues
Investigative sleuths often use the online forum PubPeer to initially raise questions about papers. The format gives the original authors a chance to comment on or defend their work. While some critiques are about data, most hone in on alleged duplications or manipulations of images, primarily by Western Blots.
The images are key, because “the images are the data,” said Dr. Rossner. “The words are the author’s interpretation of what they see in the images,” he said.
It’s also easier to spot a problem in an image. The raw data or an investigator’s notebooks aren’t needed, and there are artificial intelligence-driven software programs such as Proofig and Image Twin that help investigators spot duplicated images or cases in which an image might have been flipped or otherwise manipulated to make results look better.
Science recently announced that it would be using Proofig to screen images in all papers submitted to its six journals.
Using a screening tool is better than nothing, said Dr. Rossner who still relies on visual inspection, employing contrast or other features in PhotoShop to spot inconsistencies or duplications. But “none of those companies have disclosed how effective they are relative to visual screening, and that to me is very problematic,” he said.
“The tools are not going to catch everything,” said Dr. Bik.
Dr. Schrag agreed. “One of the things that we’re worried about is that a lot of the journals will simply adopt these tools as a screener and assume that that’s going to de-risk their publication portfolio,” he said, noting the high rate of misses.
Artificial Intelligence a Growing Concern
Artificial intelligence (AI) may also accelerate the amount of fraud and add to the difficulty of ferreting it out, said the investigators.
“I’m very worried about AI,” said Dr. Bik. Although AI-generated images and content may be rudimentary today, “next year it’s going to be much better,” she said. Going forward, it may be hard to distinguish between a real dataset and one that has been generated by AI, she said.
“The more closely AI can mimic authentic content, the more difficult it will be for publications to detect intentionally fraudulent submissions,” wrote Dror Kolodkin-Gal, PhD, the founder of Proofig, in an article for the Council of Science Editors.
Dr. Kolodkin-Gal said that AI may be especially prone to misuse by paper mills. Those operations submit fake or shoddy manuscripts to a journal on behalf of researchers seeking publication who pay the mills a fee. The Committee on Publication Ethics reported in 2022 that 2%-46% of papers submitted to journals may be from paper mills.
While it’s unclear whether AI is having any impact now, Dr. Rossner said, “I think I can be pretty confident in saying it is going to be a growing problem” as the tools become more sophisticated.
He sees parallels with the rise of PhotoShop and cites data from the National Institute of Health’s Office of Research Integrity (ORI) showing that in 1990, when PhotoShop was still new, 2% of cases referred to ORI involved image manipulation. By 2007, 70% of cases had image manipulation issues.
Journals, Institutions Need to Step Up More
Fraud may continue apace in part because investigations drag on for years, and in many cases, with a lack of consequences for the perpetrators, said the investigators. And, they say, journals and institutions haven’t devoted enough resources to prevent or investigate misconduct.
“A lot of editors did not even want to investigate because they just didn’t want to believe that there could be fraud in science,” said Dr. Bik of her experiences. “I hope that by now most journals at least should have realized that some proportion of the manuscripts that get sent to their journals is going to be fraud,” she said.
“The bulk of the journals seem like they don’t want to be bothered by this,” agreed Dr. Schrag, adding that “some have gone to great lengths to try to discourage people from bringing forward complaints.”
A big issue is that journals “don’t answer to any higher authority,” said Dr. Schrag. He believes that journals that repeatedly refuse to address integrity issues should be barred from publishing research produced with funds from the National Institutes of Health.
All the investigators said institutions and journals should hire forensic investigators. Relying on unpaid peer reviewers or editors to root out fraud is unrealistic, they said.
“You want to have specialized people with experience and be paid to do that as a full-time job,” said Dr. Bik, who is funded by speaking engagements and receives about $2300 a month through donations to her Patreon account.
Once a potential integrity issue is flagged, there is “an incredible conflict of interest in how these investigations are run,” said Dr. Schrag. “Institutions are asked to investigate their own faculty; they’re asked to investigate themselves.” That “creates the disincentive to move expeditiously,” said Dr. Schrag.
With the space of time, people who have committed fraud can throw out notebooks, delete data from servers, or even PhotoShop original photos so they match the manipulated ones that were submitted, Dr. Bik said.
Institutions could show they are serious about fraud by offering a “central, systematic universal screening of all image data going out of their institutions before submission to a journal,” said Dr. Rossner. But he knows only of a handful that do so. “I think research integrity offices have historically been very reactive, and they need to pivot and become proactive,” said Dr. Rossner.
Dr. Schrag wants to see stronger values within the research enterprise. “You have to build a culture where it’s absolutely anathema at a core level to violate these standards of research integrity,” he said. “We have this notion that we can push the process along faster and get to a grant and get to a paper and get to some short-term goal,” he said. “But the long-term goal in most of these cases is to cure a disease or to understand some biological mysteries. There’s no shortcut to getting there,” said Dr. Schrag.
There have been some high-profile consequences for research integrity failures, such as the 2023 resignation of Stanford University President Marc Tessier-Lavigne in the wake of findings that members of his lab — but not Tessier-Lavigne — engaged in data manipulation.
The process is often opaque, with investigations done in secrecy. “Consequences are not usually revealed, either,” said Dr. Rossner.
Dr. Schrag acknowledges it’s a tough balancing act for institutions to root out bad actors while also ensuring there’s no harm to those who may simply have operated in error.
“But it doesn’t serve anyone’s interest including the people who are accused, in dragging these things out for 5, 6, 8, or 10 years,” he said.
Lesne and Cassava: The Long and Winding Road
The investigations into the Lesne papers and the work underpinning Cassava Sciences’ therapy point to the difficulty of policing integrity and the potential fallout.
Lesne’s signature paper published in Nature in 2006 has been cited some 2300 times and is the fourth most-accessed article of 81,612 articles of a similar age in all journals tracked by Altimetrics.
Dr. Schrag, Dr. Bik, and others wrote to multiple journals asking them to investigate some 25 papers related to simufilam, including a 2012 Journal of Clinical Investigation article by Hoau-Yan Wang, PhD, the CUNY scientist whose work on simufilam has been questioned.
JCI Editor Elizabeth McNally pushed back stating in an editorial in 2022 that they, as whistleblowers, had potential conflicts and that they could be assisting short sellers who were seeking to profit by depressing Cassava’s stock price. Indeed, Dr. Schrag was initially hired by a law firm that was representing short sellers. Ms. McNally said that JCI would start requiring disclosures by whistleblowers.
Dr. Bik urged CUNY to investigate Dr. Wang in 2021 but was rebuffed. Then, in November 2023, a copy of CUNY’s final report on the Wang inquiry was leaked to Science. The university reported that Dr. Wang did not provide any original data or notebooks and that it found “long-standing and egregious misconduct in data management and record keeping by Dr. Wang,” wrote Dr. Bik in a blog post summarizing the investigation.
As of late 2023, 42 papers by Dr. Wang have earned PubPeer posts, seven have been retracted, and five have been marked with an Expression of Concern, wrote Dr. Bik.
Some have called for Cassava to stop its phase 3 studies of simufilam, but the company is proceeding, announcing in November 2023 that they have completed enrollment.
Misconduct Queries Underway at USC and Temple
Meanwhile, Dr. Schrag and Dr. Bik continue sleuthing. They are among a small group of whistleblowers who have filed a complaint with NIH about irregularities in the Zlokovic lab at USC. They allege that images were manipulated in dozens of papers, including some that inform the development of a stroke drug in phase 2 trials.
The inquiry goes well beyond stroke, said Dr. Schrag. Dr. Zlokovic “is one of the most influential scientists on Alzheimer’s scientists in the country,” Dr. Schrag said. The USC scientist is a leader on blood-brain barrier research.
USC is investigating “at some level,” he said. In a statement to this news organization, USC said that it “takes any allegations about research integrity very seriously.” The statement added, “Consistent with federal regulations and USC policies, this review must be kept confidential. As a result, we are unable to provide any further information.”
Mu Yang, PhD, assistant professor of neurobiology at Columbia University Medical Center in New York City, is also working on the Zlokovic investigation.
She calls herself an “accidental sleuth” who fell into the hobby after a graduate student asked her to help replicate a study by Temple University, Philadelphia, Pennsylvania, researcher Dominco Pratico, MD, of Alzheimer’s-like phenotype mice in the Morris Water Maze test. Dr. Yang, who runs the “behavior core” at Columbia — teaching and advising on how to run assays and collect and report data — could see right away that the Pratico data were “too perfect.”
She enlisted maze inventor Richard Morris to join her in a letter of concern to the journals that published Dr. Pratico’s work, all under the aegis of Springer Nature.
The publisher’s integrity team has since retracted four Pratico papers. Three were because of image abnormalities pointed out by Dr. Bik, who worked with Dr. Yang. One was because of “self-plagiarism.”
“The official retraction notes didn’t mention anything about data abnormality being a concern,” said Dr. Yang who says that questionable data is harder to prove than an image duplication or manipulation. And the papers remain available, although dozens of Practico papers have been flagged on PubPeer.
To Dr. Yang, images are the canary in the coalmine. “People don’t just fake western blots but then give real behavior data or give you fake behavior data but give you the most authentic Western Blots,” she said.
Dr. Pratico has now sued a graduate student who was a coauthor on the papers, according to the Philadelphia Inquirer.
The NIH’s ORI has requested that Temple University conduct an investigation, Dr. Yang said.
In a statement to this news organization, Temple said it “does not comment on internal investigations or personnel issues,” but that “allegations of research misconduct are reviewed and investigated centrally through Temple’s Office of the Vice President for Research in accordance with university policy and applicable federal regulations.”
A version of this article appeared on Medscape.com.
New Data Support Viagra for Alzheimer’s Prevention
The large real-world analysis of patient data from two databases showed a 30%-54% reduced prevalence in Alzheimer’s disease among patients who took sildenafil (Viagra) than those who did not, after adjusting for potential confounding factors.
This observation was further supported by mechanistic studies showing decreased neurotoxic protein levels in brain cells exposed to the phosphodiesterase type 5 inhibitor (PDE5i).
“Our findings provide further weight to repurposing this existing FDA-approved drug as a novel treatment for Alzheimer’s, which is in great need of new therapies,” Feixiong Cheng, PhD, director of the Cleveland Clinic Genome Center, who led the research, said in a news release.
“We used artificial intelligence to integrate data across multiple domains which all indicated sildenafil’s potential against this devastating neurological disease,” Dr. Cheng noted.
The study was published online in the Journal of Alzheimer’s Disease.
Neuroprotective?
Using real-world patient data from the MarketScan Medicare Supplemental database (2012-2017) and the Clinformatics database (2007-2020), the researchers conducted propensity score-stratified analyses after adjusting for gender, age, race, and comorbidities.
They searched for all individuals with pharmacy claims for sildenafil or four comparator drugs — bumetanide, furosemide, spironolactone, and nifedipine. Results showed that sildenafil use was associated with reduced likelihood of Alzheimer’s disease relative to the control drugs.
For example, sildenafil use was associated with a 54% reduced incidence of Alzheimer’s disease in MarketScan (hazard ratio [HR], 0.46; 95% CI, 0.32-0.66) and a 30% reduced prevalence of Alzheimer’s disease in Clinformatics (HR, 0.70; 95% CI, 0.49-1.00) compared with spironolactone.
The findings support a study published earlier this year that found a potential protective effect of PDE5i treatment on Alzheimer’s disease risk.
However, this research and the current study are contradicted by another paper published in Brain Communications in late 2022 which showed no such link between ED meds and reduced Alzheimer’s disease risk.
The investigators also found that sildenafil reduces tau hyperphosphorylation (pTau181 and pTau205) in a dose-dependent manner in both familial and sporadic Alzheimer’s disease patient induced pluripotent stem cell (iPSC)-derived neurons.
They further demonstrated through RNA-sequencing data analysis that sildenafil specifically targets Alzheimer’s disease related genes and pathobiological pathways, mechanistically supporting the beneficial effect of sildenafil in Alzheimer’s disease.
“We believe our findings provide the evidence needed for clinical trials to further examine the potential effectiveness of sildenafil in patients with Alzheimer’s disease,” Dr. Cheng said.
The study was primarily supported by the National Institute on Aging (NIA) and the National Institute of Neurological Disorders and Stroke (NINDS). Dr. Cheng had no relevant disclosures.
A version of this article appeared on Medscape.com.
The large real-world analysis of patient data from two databases showed a 30%-54% reduced prevalence in Alzheimer’s disease among patients who took sildenafil (Viagra) than those who did not, after adjusting for potential confounding factors.
This observation was further supported by mechanistic studies showing decreased neurotoxic protein levels in brain cells exposed to the phosphodiesterase type 5 inhibitor (PDE5i).
“Our findings provide further weight to repurposing this existing FDA-approved drug as a novel treatment for Alzheimer’s, which is in great need of new therapies,” Feixiong Cheng, PhD, director of the Cleveland Clinic Genome Center, who led the research, said in a news release.
“We used artificial intelligence to integrate data across multiple domains which all indicated sildenafil’s potential against this devastating neurological disease,” Dr. Cheng noted.
The study was published online in the Journal of Alzheimer’s Disease.
Neuroprotective?
Using real-world patient data from the MarketScan Medicare Supplemental database (2012-2017) and the Clinformatics database (2007-2020), the researchers conducted propensity score-stratified analyses after adjusting for gender, age, race, and comorbidities.
They searched for all individuals with pharmacy claims for sildenafil or four comparator drugs — bumetanide, furosemide, spironolactone, and nifedipine. Results showed that sildenafil use was associated with reduced likelihood of Alzheimer’s disease relative to the control drugs.
For example, sildenafil use was associated with a 54% reduced incidence of Alzheimer’s disease in MarketScan (hazard ratio [HR], 0.46; 95% CI, 0.32-0.66) and a 30% reduced prevalence of Alzheimer’s disease in Clinformatics (HR, 0.70; 95% CI, 0.49-1.00) compared with spironolactone.
The findings support a study published earlier this year that found a potential protective effect of PDE5i treatment on Alzheimer’s disease risk.
However, this research and the current study are contradicted by another paper published in Brain Communications in late 2022 which showed no such link between ED meds and reduced Alzheimer’s disease risk.
The investigators also found that sildenafil reduces tau hyperphosphorylation (pTau181 and pTau205) in a dose-dependent manner in both familial and sporadic Alzheimer’s disease patient induced pluripotent stem cell (iPSC)-derived neurons.
They further demonstrated through RNA-sequencing data analysis that sildenafil specifically targets Alzheimer’s disease related genes and pathobiological pathways, mechanistically supporting the beneficial effect of sildenafil in Alzheimer’s disease.
“We believe our findings provide the evidence needed for clinical trials to further examine the potential effectiveness of sildenafil in patients with Alzheimer’s disease,” Dr. Cheng said.
The study was primarily supported by the National Institute on Aging (NIA) and the National Institute of Neurological Disorders and Stroke (NINDS). Dr. Cheng had no relevant disclosures.
A version of this article appeared on Medscape.com.
The large real-world analysis of patient data from two databases showed a 30%-54% reduced prevalence in Alzheimer’s disease among patients who took sildenafil (Viagra) than those who did not, after adjusting for potential confounding factors.
This observation was further supported by mechanistic studies showing decreased neurotoxic protein levels in brain cells exposed to the phosphodiesterase type 5 inhibitor (PDE5i).
“Our findings provide further weight to repurposing this existing FDA-approved drug as a novel treatment for Alzheimer’s, which is in great need of new therapies,” Feixiong Cheng, PhD, director of the Cleveland Clinic Genome Center, who led the research, said in a news release.
“We used artificial intelligence to integrate data across multiple domains which all indicated sildenafil’s potential against this devastating neurological disease,” Dr. Cheng noted.
The study was published online in the Journal of Alzheimer’s Disease.
Neuroprotective?
Using real-world patient data from the MarketScan Medicare Supplemental database (2012-2017) and the Clinformatics database (2007-2020), the researchers conducted propensity score-stratified analyses after adjusting for gender, age, race, and comorbidities.
They searched for all individuals with pharmacy claims for sildenafil or four comparator drugs — bumetanide, furosemide, spironolactone, and nifedipine. Results showed that sildenafil use was associated with reduced likelihood of Alzheimer’s disease relative to the control drugs.
For example, sildenafil use was associated with a 54% reduced incidence of Alzheimer’s disease in MarketScan (hazard ratio [HR], 0.46; 95% CI, 0.32-0.66) and a 30% reduced prevalence of Alzheimer’s disease in Clinformatics (HR, 0.70; 95% CI, 0.49-1.00) compared with spironolactone.
The findings support a study published earlier this year that found a potential protective effect of PDE5i treatment on Alzheimer’s disease risk.
However, this research and the current study are contradicted by another paper published in Brain Communications in late 2022 which showed no such link between ED meds and reduced Alzheimer’s disease risk.
The investigators also found that sildenafil reduces tau hyperphosphorylation (pTau181 and pTau205) in a dose-dependent manner in both familial and sporadic Alzheimer’s disease patient induced pluripotent stem cell (iPSC)-derived neurons.
They further demonstrated through RNA-sequencing data analysis that sildenafil specifically targets Alzheimer’s disease related genes and pathobiological pathways, mechanistically supporting the beneficial effect of sildenafil in Alzheimer’s disease.
“We believe our findings provide the evidence needed for clinical trials to further examine the potential effectiveness of sildenafil in patients with Alzheimer’s disease,” Dr. Cheng said.
The study was primarily supported by the National Institute on Aging (NIA) and the National Institute of Neurological Disorders and Stroke (NINDS). Dr. Cheng had no relevant disclosures.
A version of this article appeared on Medscape.com.
FROM THE JOURNAL OF ALZHEIMER’S RESEARCH
Air Pollution Tied to Greater Amyloid Burden in the Brain
TOPLINE:
, a new postmortem study showed.
METHODOLOGY:
- Investigators examined the brain tissue of 224 people living in the Atlanta area who agreed to donate their brains after death (average age of death, 76 years) for the presence of amyloid plaques and tau tangles.
- They also studied the amount of fine particulate matter < 2.5 microns (PM2.5) from traffic-related air pollution at participants’ home addresses at 1, 3, and 5 years before death.
- The presence of the APOE e4 gene was examined for evidence of any effect on the relationship between air pollution and evidence of Alzheimer’s disease (AD).
TAKEAWAY:
The average level of exposure in the year before death was 1.32 µg/m3 and 1.35 µg/m3 in the 3 years before death.
People with 1 µg/m3 higher PM2.5 exposure in the year before death were nearly twice as likely to have higher levels of plaques (odds ratio [OR], 1.92; 95% CI, 1.12-3.30), while those with higher exposure in the 3 years before death were 87% more likely to have higher levels of plaques (OR, 1.87; 95% CI, 1.01-3.17).
A little more than half (56%) of the sample were positive for the APOE e4 genotype, but the strongest association between pollution and neuropathology markers was for noncarriers of the genotype, although this relationship did not reach statistical significance.
IN PRACTICE:
“More research is needed to establish causality for the association between PM2.5 and AD, including epidemiologic and mechanistic studies. Future studies should also investigate the association between PM2.5 and other dementia-related pathologies, including cerebrovascular pathology,” the study authors wrote.
SOURCE:
Anke Hüls, PhD, of Emory University in Atlanta, led the study, which was published online on February 21, 2024, in Neurology.
LIMITATIONS:
The sample was not population-based but a convenience sample composed mostly of highly educated White participants.
DISCLOSURES:
The study was funded by the National Institute of Environmental Health Sciences, the Goizueta Alzheimer’s Disease Research Center, the National Institute on Aging, and the National Institutes of Health. There were no relevant disclosures.
A version of this article appeared on Medscape.com.
TOPLINE:
, a new postmortem study showed.
METHODOLOGY:
- Investigators examined the brain tissue of 224 people living in the Atlanta area who agreed to donate their brains after death (average age of death, 76 years) for the presence of amyloid plaques and tau tangles.
- They also studied the amount of fine particulate matter < 2.5 microns (PM2.5) from traffic-related air pollution at participants’ home addresses at 1, 3, and 5 years before death.
- The presence of the APOE e4 gene was examined for evidence of any effect on the relationship between air pollution and evidence of Alzheimer’s disease (AD).
TAKEAWAY:
The average level of exposure in the year before death was 1.32 µg/m3 and 1.35 µg/m3 in the 3 years before death.
People with 1 µg/m3 higher PM2.5 exposure in the year before death were nearly twice as likely to have higher levels of plaques (odds ratio [OR], 1.92; 95% CI, 1.12-3.30), while those with higher exposure in the 3 years before death were 87% more likely to have higher levels of plaques (OR, 1.87; 95% CI, 1.01-3.17).
A little more than half (56%) of the sample were positive for the APOE e4 genotype, but the strongest association between pollution and neuropathology markers was for noncarriers of the genotype, although this relationship did not reach statistical significance.
IN PRACTICE:
“More research is needed to establish causality for the association between PM2.5 and AD, including epidemiologic and mechanistic studies. Future studies should also investigate the association between PM2.5 and other dementia-related pathologies, including cerebrovascular pathology,” the study authors wrote.
SOURCE:
Anke Hüls, PhD, of Emory University in Atlanta, led the study, which was published online on February 21, 2024, in Neurology.
LIMITATIONS:
The sample was not population-based but a convenience sample composed mostly of highly educated White participants.
DISCLOSURES:
The study was funded by the National Institute of Environmental Health Sciences, the Goizueta Alzheimer’s Disease Research Center, the National Institute on Aging, and the National Institutes of Health. There were no relevant disclosures.
A version of this article appeared on Medscape.com.
TOPLINE:
, a new postmortem study showed.
METHODOLOGY:
- Investigators examined the brain tissue of 224 people living in the Atlanta area who agreed to donate their brains after death (average age of death, 76 years) for the presence of amyloid plaques and tau tangles.
- They also studied the amount of fine particulate matter < 2.5 microns (PM2.5) from traffic-related air pollution at participants’ home addresses at 1, 3, and 5 years before death.
- The presence of the APOE e4 gene was examined for evidence of any effect on the relationship between air pollution and evidence of Alzheimer’s disease (AD).
TAKEAWAY:
The average level of exposure in the year before death was 1.32 µg/m3 and 1.35 µg/m3 in the 3 years before death.
People with 1 µg/m3 higher PM2.5 exposure in the year before death were nearly twice as likely to have higher levels of plaques (odds ratio [OR], 1.92; 95% CI, 1.12-3.30), while those with higher exposure in the 3 years before death were 87% more likely to have higher levels of plaques (OR, 1.87; 95% CI, 1.01-3.17).
A little more than half (56%) of the sample were positive for the APOE e4 genotype, but the strongest association between pollution and neuropathology markers was for noncarriers of the genotype, although this relationship did not reach statistical significance.
IN PRACTICE:
“More research is needed to establish causality for the association between PM2.5 and AD, including epidemiologic and mechanistic studies. Future studies should also investigate the association between PM2.5 and other dementia-related pathologies, including cerebrovascular pathology,” the study authors wrote.
SOURCE:
Anke Hüls, PhD, of Emory University in Atlanta, led the study, which was published online on February 21, 2024, in Neurology.
LIMITATIONS:
The sample was not population-based but a convenience sample composed mostly of highly educated White participants.
DISCLOSURES:
The study was funded by the National Institute of Environmental Health Sciences, the Goizueta Alzheimer’s Disease Research Center, the National Institute on Aging, and the National Institutes of Health. There were no relevant disclosures.
A version of this article appeared on Medscape.com.